tbuckley/cabot-search huggingface dataset:
Abstract 912: uPA as a topoisomerase-1 protective agent in lung fibroblast cells
Authors: Liang Ge, Manu Gnanamony, Victoria Stepanova, Dzung H. Dinh, Christopher S. Gondi
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, with approximately 53,000 people in the U.S. diagnosed with the disease every year. The Gondi lab has previously shown that poor survival rates in pancreatic cancer are correlated with increased expression of urokinase plasminogen activator (uPA), a serine protease. Our previous data has shown for the first time that uPA binds to topoisomerase-1 (TOPO-1), in addition to the interaction of uPA with various transcription factors. Our current research is aimed at elucidating the mechanism of the interaction between uPA and TOPO-1, with the goal of demonstrating a protective role for uPA in the regulation of TOPO-1 function in the presence of TOPO-1 inhibitors. Methods: Two knock-out lung fibroblast cell lines were used. One cell line was a uPA knock-out line, while the other was a uPA knock-out line with a uPA expression vector transfected into the cells. Transfection was performed using Chariot transfection vector. The cell lines were treated with topoisomerase inhibitors TX1111 and SN38. DNA replication activity was measured using flow cytometry as a surrogate for TOPO-1 activity. Controls included untreated cells, cells treated with empty Chariot, and cells treated with Chariot containing TXC peptide. Results and Discussion: In the presence of topoisomerase inhibitors TX1111 and SN38, uPA knock-out lines demonstrated incomplete cell division relative to controls. In uPA-expressing lines, cell division activity was retained in the presence of topoisomerase inhibitors. Our data demonstrates for the first time that uPA serves a protective role in preventing the inhibition of TOPO-1 by topoisomerase inhibitors. This indicates uPA as a potential new drug target in the treatment of chemoresistant pancreatic cancer. Further studies to be performed include visualizing the degree of DNA-replication using DNA combing, and subsequently expanding this study to pancreatic cancer cells. Citation Format: Liang Ge, Manu Gnanamony, Victoria Stepanova, Dzung H. Dinh, Christopher S. Gondi. uPA as a topoisomerase-1 protective agent in lung fibroblast 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 912.
Safety and activity of nonpegylated liposomal doxorubicin (nPLD) combined with oral metronomic cyclophosphamide (mC) as preoperative treatment for locally advanced breast cancer (BC) patients (pts).
Authors: Daniele Andreis, Daniele Giulio Generali, Chiara Foroni, Letizia Bazzola, Mariarosa Cappelletti, Vanessa Zanoni, Manuela Milani, Carla Strina, Giovanni Allevi, Sergio Aguggini, Ermenegilda Boni, Roberto Giardini, Ramona Bertoni, Alberto Bottini
Journal: Journal of Clinical Oncology (2012)

e11546 Background: nPLD has the same clinical benefits but less toxicity than the traditional doxorubicin. It’s well reported mC produces anti-proliferative and anti-angiogenic effect in tumours. We conducted a retrospective study to evaluate the safety and activity of the association of nPLD and mC in pts with locally advanced BC. Methods: A total of 41 female pts with HER2-negative locally advanced BC unfit for standard chemotherapy received nPLD 25 mg/mq biweekly for eight courses along with mC 50 mg daily as primary systemic treatment. Toxicity and clinical-radiological response with Ki67 and CD31 expression were evaluated in tumour specimens obtained before and after treatment. Results: Pts characteristics included: median age 47.5 years; 31.7% Luminal A (LA), 56.1% Luminal B (LB), and 12.2% Triple Negative BC subtype classified by immunohistochemistry. The rate of breast-conserving surgery was 59.5%. All pts were evaluable for response. Objective response rate (ORR) was 58.5% (95% confidence interval, 42.1% to 73.7%), with 4 (9.7%) clinical complete responses (CR) and 20 (48.8%) partial responses. Sixteen pts (39.0%) achieved a stable disease and 1 pt progressed. One pt experienced a pathological CR. LA subtype was significantly associated with better ORR than others subtypes (p=0.049) and especially than LB (p=0.040). There was a borderline significant reduction of Ki67 expression after treatment (median, 15.5% to 9%; p=0.056), but no significant variation in CD31 expression (p=0.865). The majority of adverse events (AEs) were mild or moderate. Grade ≥3 AEs included neutropenia (12.2%), vomiting (4.9%) and hyperglycemia (2.44%). Temporary treatment suspension due to toxicity occurred in 8 (19.5%) pts; discontinuation was necessary in 1 pt. No symptoms were related to impairment of cardiac function. Mean left ventricular ejection fraction levels did not change substantially before and after treatment: 58.7% and 57.1%, respectively. Conclusions: The combination of nPLD and mC is well tolerated, with a promising activity as preoperative therapy in unfit pts with locally advanced BC.
Shear Stress–Dependent Regulation of the Human β-Tubulin Folding Cofactor D Gene
Authors: AndreasSchubert, MarcoCattaruzza, MarkusHecker, DorotheaDarmer, JuergenHoltz, HenningMorawietz
Journal: Circulation Research (2000)

Abstract—The flowing blood generates shear stress at the endothelial cell surface. The endothelial cells modify their phenotype by alterations in gene expression in response to different levels of fluid shear stress. To identify genes involved in this process, human umbilical vein endothelial cells were exposed to laminar shear stress (venous or arterial levels) in a cone-and-plate apparatus for 24 hours. Using the method of RNA arbitrarily primed polymerase chain reaction, we cloned a polymerase chain reaction fragment representing an mRNA species downregulated by arterial compared with venous shear stress (shear stress downregulated gene-1, SSD-1). According to Northern blot analysis, corresponding SSD-1 cDNA clones revealed a similar, time-dependent downregulation after 24 hours of arterial shear stress compared with venous shear stress or static controls. Three SSD-1 mRNA species of 2.8, 4.1, and 4.6 kb were expressed in a tissue-specific manner. The encoded amino acid sequence of the human endothelia...
Improved Survival After Out-of-Hospital Cardiac Arrest Is Associated With an Increase in Proportion of Emergency Crew–Witnessed Cases and Bystander Cardiopulmonary Resuscitation
Authors: JacobHollenberg, JohanHerlitz, JonnyLindqvist, GabrielRiva, KatarinaBohm, MårtenRosenqvist, LeifSvensson
Journal: Circulation (2008)

Background— Out-of-hospital cardiac arrest (OHCA) is a major public health problem. We sought to describe changes in 1-month survival after OHCA in patients given cardiopulmonary resuscitation (CPR) during the last 14 years in Sweden. Methods and Results— All patients experiencing OHCA in whom CPR was attempted between 1992 and 2005 and who were reported to the Swedish Cardiac Arrest Register were included in the study. In all, 38 646 patients were included in this survey. The proportion of patients who were admitted alive to a hospital increased from 15.3% in 1992 to 21.7% in 2005 (P for trend <0.0001). The corresponding values for patients being alive after 1 month were 4.8% and 7.3%, respectively (P for trend <0.0001). The increase in 1-month survival was particularly evident among patients found with a shockable rhythm (increase from 12.7% in 1992 to 22.3% in 2005; P for trend <0.0001). The corresponding figures for patients found with a nonshockable rhythm were 1.2% in 1992 and 2.3% in 2005 (P for tr...
Extracellular Mg2+ Inhibits Capacitative Ca2+ Entry in Vascular Smooth Muscle Cells
Authors: MitsuisaYoshimura, TetsuyaOshima, HideoMatsuura, TakafumiIshida, MasayukiKambe, GoroKajiyama
Journal: Circulation (1997)

Background Agonist-induced Ca2+ entry is thought to be mediated by capacitative Ca2+ entry other than L-type Ca2+ channels in vascular smooth muscle cells (VSMCs). The mechanism for capacitative Ca2+ entry has not been fully elucidated. Our objective was to examine the effect of external Mg2+ on capacitative Ca2+ entry in cultured rat aortic VSMCs. Methods and Results Three doses of external Mg2+ concentration (nominally 0, 1, and 5 mmol/L) were used. After exposure to 1 μmol/L angiotensin II (Ang II) in Ca2+-free medium, addition of Ca2+ to the medium caused an increase in cytosolic free Ca2+ concentration ([Ca2+]i), indicating Ang II–induced Ca2+ influx. This Ca2+ influx was attenuated in cells preincubated with high external Mg2+ concentrations or with 1 μmol/L nifedipine. After VSMCs in Ca2+-free medium were exposed to 1 μmol/L thapsigargin, which inhibits the sarcoplasmic reticulum Ca2+-ATPase and depletes Ca2+ stores, addition of Ca2+ to the medium induced an increase in [Ca2+]i, indicating capacita...
Persistent Renal Damage After Contrast-Induced Acute Kidney Injury
Authors: MauroMaioli, AnnaToso, MarioLeoncini, MichelaGallopin, NicolaMusilli, FrancescoBellandi
Journal: Circulation (2012)

Background—The temporal evolution of renal function in patients with acute kidney injury after contrast medium (CI-AKI) is not well known. The aim of this observational study was to evaluate the incidence, risk factors, and prognostic implications of persistent renal damage (RD) in patients with preexistent moderate-to-severe renal dysfunction. Methods and Results—From June 2003 to March 2008, 3986 patients underwent coronary angiography at our institution; 1490 of 3986 had an estimated creatinine clearance of <60 mL/min and were enrolled. CI-AKI was defined as an absolute increase ≥0.5 mg/dL over baseline serum creatinine within 3 days after the administration of contrast medium (iodixanol). In patients who developed CI-AKI, persistent RD was defined as a relative decrease of creatinine clearance ≥25% over baseline at 3 months. Patients whose creatinine clearance returned to baseline (or nearly) were classified as transient RD. The overall incidence of CI-AKI was 12.1%, and persistent RD occurred in 18.6...
Tat-functionalized Ag-Fe3O4 nano-composites as tissue-penetrating vehicles for tumor magnetic targeting and drug delivery
Authors: Ergang Liu, Meng Zhang, Hui Cui, Junbo Gong, Yongzhuo Huang, Jianxin Wang, Yanna Cui, Weibing Dong, Lu Sun, Huining He, Victor C. Yang
Journal: Acta Pharmaceutica Sinica B (2018)

In this paper, we prepared a dual functional system based on dextrin-coated silver nanoparticles which were further attached with iron oxide nanoparticles and cell penetrating peptide (Tat), producing Tat-modified Ag-Fe3O4 nanocomposites (Tat-FeAgNPs). To load drugs, an –SH containing linker, 3-mercaptopropanohydrazide, was designed and synthesized. It enabled the silver carriers to load and release doxorubicin (Dox) in a pH-sensitive pattern. The delivery efficiency of this system was assessed in vitro using MCF-7 cells, and in vivo using null BalB/c mice bearing MCF-7 xenograft tumors. Our results demonstrated that both Tat and externally applied magnetic field could promote cellular uptake and consequently the cytotoxicity of doxorubicin-loaded nanoparticles, with the IC50 of Tat-FeAgNP-Dox to be 0.63 µmol/L. The in vivo delivery efficiency of Tat-FeAgNP carrying Cy5 to the mouse tumor was analyzed using the in vivo optical imaging tests, in which Tat-FeAgNP-Cy5 yielded the most efficient accumulation in the tumor (6.7±2.4% ID of Tat-FeAgNPs). Anti-tumor assessment also demonstrated that Tat-FeAgNP-Dox displayed the most significant tumor-inhibiting effects and reduced the specific growth rate of tumor by 29.6% (P = 0.009), which could be attributed to its superior performance in tumor drug delivery in comparison with the control nanovehicles.
Abstract 2509: Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast cancer
Authors: Ji Young Kim, Eunhye Oh, Yoon-Jae Kim, Daeil Sung, Tae-Min Cho, Seojin Jang, Jae Hong Seo
Journal: Cancer Research (2018)

Abstract The angiotensin II type I receptor (AGTR1) has been implicated in diverse aspects of human disease, from the regulation of blood pressure and cardiovascular homeostasis. A recent study has reported pathogenic overexpression of the angiotensin II type 1 receptor (AGTR1) in breast cancers. We sought to investigate the effect of losartan, an angiotensin II receptor blocker on cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis and tumor growth in breast cancer. Overexpression of AGTR1 was associated with accelerated cell proliferation, concomitant with increased expression of survival factors including poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), as well as extracellular signal-regulated kinase (ERK) activation. AGTR1-overexpressing MCF7 cells were more aggressive than their parent line, with significantly increased activity in migration and invasion assays. These observations were associated with changes in EMT markers, including reduced E-cadherin expression and increased p-Smad3, Smad4 and Snail levels. Treatment with the AGTR1 antagonist losartan attenuated these effects in vitro. To confirm the physiological relevance of our in vitro observations, we examined the effect of losartan on tumor growth using a mammary fat pad xenograft model with the AGTR1-overexpressing cells. Losartan administration resulted in a significant reduction in tumor growth and a significant decrease in the number of Ki-67-positive cells in the AGTR1-overexpressing xenograft tumors. Losartan administration notably upregulated E-cadherin and suppressed vimentin expression. Furthermore, microvessel density analysis revealed that the number of CD31-positive microvessels in both the peritumoral and intratumoral areas was significantly decreased in the losartan-treated groups. Our findings support the notion that AGTR1 is a potentially useful diagnostic marker and its inhibition may provide an effective therapeutic strategy for breast cancer treatment. Citation Format: Ji Young Kim, Eunhye Oh, Yoon-Jae Kim, Daeil Sung, Tae-Min Cho, Seojin Jang, Jae Hong Seo. Blockage of angiotensin II type 1 receptor (AGTR1) inhibits epithelial-mesenchymal transition (EMT) and tumor growth in breast 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 2509.
Abstract 5292: Visceral adiposity-stimulated genotoxicity and malignant transformation of epithelial cells
Authors: Debrup Chakraborty, Vladislav Jdanov, Vanessa Benham, Blair Bullard, Jamie J. Bernard
Journal: Cancer Research (2018)

Abstract Obesity is a global epidemic with a predicted rate of 42% in the U.S.A by 2050. Epidemiologic studies show that obesity is a risk factor for developing cancer; however, the molecular mechanism has not been fully elucidated. Our published data demonstrate that fibroblast growth factor-2 (FGF2) released from fat cells (adipocytes) in the visceral adipose tissue (VAT) induces transformation/tumorigenicity in the skin and mammary epithelial cells. Specifically, FGF2 released from VAT stimulates epithelial cell growth in soft agar by inducing the proto-oncogene c-Myc. Growth in soft agar is a measure of transformation/tumorigenicity; neither transformation nor c-Myc induction in epithelial cells was reversible. c-Myc overexpression can initiate a process of genetic instability linked to tumor initiation. Our discovery of this novel direct path of VAT-stimulated tumorigenesis adds mechanistic insight to our earlier discovery that VAT secretions promote UVR-induced nonmelamoma skin cancer. The objective of our current study was to determine the mechanism by which FGF2 stimulates malignant transformation. We hypothesized that FGF2 from VAT induces c-Myc and subsequent genomic instability in epithelial cells, leading to increased carcinogenesis. To test hypothesis we generated a filtered conditioned-medium from the human VAT treated MCF-10A (mammary epithelial) and JB6 P+ (skin epithelial) cells and measured several downstream mediators of FGF2 and activation of FGFR-1 (FGF2 receptor). Following VAT treatment, epithelial cells demonstrated induced c-Myc protein expression along with ROS accumulation, elevated γ-H2AX foci, and increased micronucleus (MN) formation. We found that inhibition of c-Myc attenuated VAT-induced neoplastic transformation of MCF-10A and JB6 P+ cells, while constitutive activation of the c-Myc-induced spontaneous neoplastic transformation of JB6 P+ cells. Collectively, our data suggested FGF2 released from VAT interacts with FGFR-1 and activates c-Myc. The role of c-Myc in the formation of MN and DNA damage is under investigation. Determining the impact of excess VAT on cancer will lead to strategies to help prevent adiposity-associated cancers and identify individuals at risk for disease or individuals who may be susceptible to compounded genotoxicity due to DNA-damaging environmental exposures. Citation Format: Debrup Chakraborty, Vladislav Jdanov, Vanessa Benham, Blair Bullard, Jamie J. Bernard. Visceral adiposity-stimulated genotoxicity and malignant transformation of epithelial 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 5292.
Alternatively Spliced IS6 Segments of the α1C Gene Determine the Tissue-Specific Dihydropyridine Sensitivity of Cardiac and Vascular Smooth Muscle L-Type Ca2+ Channels
Authors: AndreaWelling, AndreasLudwig, StephanieZimmer, NorbertKlugbauer, VeitFlockerzi, FranzHofmann
Journal: Circulation Research (1997)

Abstract Dihydropyridines (DHPs) block the vascular smooth muscle L-type Ca2+ channel at lower concentrations than the cardiac Ca2+ channel, although their α1 subunit, which binds the DHPs, is derived from the same gene. This α1C gene gives rise to several splice variants, among which the α1C-b variant is affected by lower concentrations of nisoldipine than the α1C-a variant. Functional expression of chimeras of α1C-a and α1C-b subunits demonstrated that the transmembrane segment IS6 is responsible for the different dihydropyridine sensitivity. Northern blot analysis showed that transcripts coding for the IS6 segment of the α1C-a subunit were expressed in heart but not in aorta, whereas the IS6 segment of the α1C-b subunit was expressed predominantly in vascular smooth muscle. In situ hybridization of rat heart sections confirmed this expression pattern of IS6 α1C-a and IS6 α1C-b in ventricular and smooth muscle myocytes, respectively. These results suggest that the different dihydropyridine sensitivities...
Abstract 144: Dasatinib enhances the effects of paclitaxel on chemotherapy-resistant breast cancer through targeting breast cancer stem cells
Authors: Jun Tian, Chieh Lo, Fatmah Al Raffa, Meiou Dai, Jean-Jacques Lebrun
Journal: Cancer Research (2018)

Abstract Many patients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumor relapse and metastasis due to the resistance to conventional chemotherapy. These tumor recurrences have been attributed to the presence of breast cancer stem cells (BCSCs), a subpopulation of breast cancer cells that possesses stem-like properties and displays resistance to chemotherapy. Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs. We generated chemotherapy-resistant TNBC cells through cyclic treatments with paclitaxel (pac). The pac-resistant cells displayed increased self-renewal potential compared to the parental TNBC cells, higher percentage BCSCs and increased phosphorylation of Src kinase at Tyr416. After performing a kinase library screening on BCSCs in chemotherapy-resistant cells, we identified dasatinib, a Src kinase family inhibitor, potently reduced BCSC self-renewal and two BCSC populations (ALDH+ and CD24lowCD44high) as well as phosphor-Src. We also demonstrated dasatinib to block pac-induced BCSC enrichment and Src activation in the parental TNBC cells. Interestingly, we found that dasatinib induced an epithelial differentiation of pac-resistant cells, resulting in their enhanced sensitivity to paclitaxel. The combination treatment of dasatinib and paclitaxel not only decreased the proportion of BCSCs and their self-renewal capacity but also synergistically reduced cell viability of pac-resistant cells. In vivo studies further demonstrated the effectiveness of dasatinib/paclitaxel combination treatment in inhibiting breast tumor growth. All these data suggest that dasatinib is a promising anti-BCSC agent and can be used in combination with paclitaxel to overcome chemotherapy resistance in TNBCs. Citation Format: Jun Tian, Chieh Lo, Fatmah Al Raffa, Meiou Dai, Jean-Jacques Lebrun. Dasatinib enhances the effects of paclitaxel on chemotherapy-resistant breast cancer through targeting breast cancer stem 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 144.
Endothelial Cytotoxicity Mediated by Serum Antibodies to Heat Shock Proteins of Escherichia coli and Chlamydia pneumoniae
Authors: ManuelMayr, BernhardMetzler, StefanKiechl, JohannWilleit, GeorgSchett, QingboXu, GeorgWick
Journal: Circulation (1999)

Background—Growing evidence suggests that an immunological reaction against heat shock proteins (HSPs) may be involved in atherogenesis. Because HSPs show a high degree of amino acid sequence homology between different species, from prokaryotes to humans, we investigated the possibility of “antigenic mimicry” caused by an immunological cross-reaction between microorganisms and autoantigens. Methods and Results—Serum antibodies against the Escherichia coli HSP (GroEL) and the 60-kDa chlamydial HSP (cHSP60) from subjects with atherosclerosis were purified by use of affinity chromatography. Western blot analyses and competitive ELISAs confirmed the cross-reaction of the eluted antibodies with human HSP60 and the bacterial counterparts. The cytotoxicity of anti-GroEL and anti-cHSP60 antibodies was determined on human endothelial cells labeled with 51Cr. A significant difference (40% versus 8%) was observed in the specific 51Cr release of heat-treated (42°C for 30 minutes) and untreated cells, respectively, in...
Abstract 11218: Bone Marrow Angiotensin AT2 Receptor Deficiency Aggravates Atherosclerosis by Eliminating Macrophage Liver X Receptor-Mediated Anti-Atherogenic Actions
Authors: Taku Kato, Hiroyuki Yamada, Hiroyuki Kawahito, Daisuke Irie, Kensuke Fukui, Kouji Ikeda, Mitsuhiko Okigaki, Masaki Mogi, Masaru Iwai, Masatsugu Horiuchi, Hiroaki Matsubara
Journal: Circulation (2011)

[BACKGROUND] The angiotensin II (Ang II) type 2 (AT2) receptor is crucially involved in atherogenesis; however, bone marrow (BM) AT2-mediated anti-atherogenic action remains undefined. [METHOD AND ...
Two-Photon Microscopy of Cells and Tissue
Authors: MichaelRubart
Journal: Circulation Research (2004)

Two-photon excitation fluorescence imaging provides thin optical sections from deep within thick, scattering specimens by way of restricting fluorophore excitation (and thus emission) to the focal plane of the microscope. Spatial confinement of two-photon excitation gives rise to several advantages over single-photon confocal microscopy. First, penetration depth of the excitation beam is increased. Second, because out-of-focus fluorescence is never generated, no pinhole is necessary in the detection path of the microscope, resulting in increased fluorescence collection efficiency. Third, two-photon excitation markedly reduces overall photobleaching and photodamage, resulting in extended viability of biological specimens during long-term imaging. Finally, localized excitation can be used for photolysis of caged compounds in femtoliter volumes and for diffusion measurements by two-photon fluorescence photobleaching recovery. This review aims to provide an overview of the use of two-photon excitation microsc...