tbuckley/cabot-search huggingface dataset:
Abstract 3138: Key role of secreted kinase FAM20C on tumor associated macrophage (TAM) leading to pancreatic cancer progression
Authors: Jieun Im, Yu-Sun Lee, Sun Il Choi, Beom-Kyu Choi, A-Ra Jeon, Sang Hyun Park, Min-Kyeong Lee, Joon-Ki Kim, Yun-Hee Kim
Journal: Cancer Research (2018)

Abstract FAM20C reported as a novel secreted kinase has the potential of phosphorylation on consensus motif, S-x-E/pS, of secretory proteins or ectodomain of membrane proteins. Numerous substrate candidates through prediction implied FAM20C has the function on tumor microenvironment, however, function and regulatory mechanism of cancer progression by FAM20C has not been defined yet. As tumor associated macrophage (TAM) changes to have the tumor supporting phenotype in response to various environmental stimuli, TAM is the potent regulatory target of FAM20C in tumor microenvironment. In this study, we hypothesized that the secreted kinase FAM20C in tumor microenvironment can support pancreatic cancer progression by regulating TAM contents or polarization. In pancreatic orthotopic xenograft model of FAM20C-overexpressing tumor cells, the tumor growth rate was enhanced and TAM contents (F4/80+/CD11b+/MHCII+) were significantly increased compared to control group, while total macrophage population between two groups had no difference. Moreover, the high level of TAM contents was sustained in the presence of FAM20C till the late stage of tumor progression. In addition, infiltrated tissue macrophages were polarized into TAM by FAM20C treatment Furthermore, increased TAM population by FAM20C suppresses the CD8+ cytotoxic T cell proliferation with anti-tumor function. Collectively, FAM20C might be a key regulatory factor in pancreatic cancer progression by promoting polarization of TAM. Citation Format: Jieun Im, Yu-Sun Lee, Sun Il Choi, Beom-Kyu Choi, A-Ra Jeon, Sang Hyun Park, Min-Kyeong Lee, Joon-Ki Kim, Yun-Hee Kim. Key role of secreted kinase FAM20C on tumor associated macrophage (TAM) leading to pancreatic cancer progression [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 3138.
High Plasma Heparin Cofactor II Activity Is Associated With Reduced Incidence of In-Stent Restenosis After Percutaneous Coronary Intervention
Authors: NobuyukiTakamori, HiroyukiAzuma, MidoriKato, ShunjiHashizume, Ken-ichiAihara, MasashiAkaike, KatsuyaTamura, ToshioMatsumoto
Journal: Circulation (2004)

Background— Thrombin plays an important role in the development of atherosclerosis and restenosis after percutaneous coronary intervention. Because heparin cofactor II (HCII) inhibits thrombin action in the presence of dermatan sulfate, which is abundantly present in arterial wall, HCII may affect vascular remodeling by modulating thrombin action. We hypothesized that patients with high plasma HCII activity may show a reduced incidence of in-stent restenosis (ISR). Methods and Results— Sequential coronary arteries (n=166) with NIR stent (Boston Scientific Corp) implantation in 134 patients were evaluated before, immediately after, and at 6 months after percutaneous coronary intervention. Patients were divided into the following groups: high HCII (≥110%, 45 lesions in 36 patients), normal HCII (≥80% and <110%, 81 lesions in 66 patients), and low HCII (<80%, 40 lesions in 32 patients). Percent diameter stenosis at follow-up in the high-HCII group (18.7%) was significantly lower (P=0.046) than that in the no...
Abstract 4027: Fibroblast growth factor 2 (FGF2) is associated with the development of resistance to pemetrexed in lung cancer cells
Authors: Kentaro Miura, Ken-ichi Ito, Takaaki Oba, Asumi Iesato
Journal: Cancer Research (2018)

Abstract Pemetrexed (MTA) is a folate antimetabolite used for treatment of non-small cell lung cancer and plural mesothelioma. Although several molecules such as thymidylate synthase (TS) or ATP-binding cassette transporter 11 (ABCC11) have been reported to be involved in the mechanisms of resistance to MTA, precise mechanisms underlying resistance to MTA remains unknown. To elucidate the mechanisms of resistance to MTA in lung cancer, we established MTA resistant clones in PC9 and H1993 lung adenocarcinoma cell lines (PC9-MTA, H1993-MTA). Then, gene expression profiles were compared between PC9 and PC9-MTA cells by using microarray analyses, and several genes including fibroblast growth factor 2 (FGF2) were identified. Elevated expression of FGF2 in PC9-MTA cells and H1993-MTA cells were confirmed by western blot analyses. Knockdown of FGF2 by siRNA partially restored the sensitivity to MTA both in PC9-MTA and H1993-MTA cells. In addition, anti-FGFR1 inhibitor (PD173074) restored MTA sensitivity particularly in PC9-MTA cells. On the other hand, the expression of TS was increased in PC9-MTA and H1993-MTA cells, and the inhibition of TS with the TS-targeting siRNA restored the sensitivity to MTA. However, with regard to the expression of FGF2 and TS, the inhibition of FGF2 did not modify the expression of TS, and vise versa. Furthermore, a simultaneous inhibition of FGF2 and TS by siRNAs in the MTA-resistant cells restored MTA sensitivity to approximately the level observed for the parental cell lines. With regard to the factors related to the signal transduction pathway, the phosphorylation of Erk and Akt in H1993-MTA cells was decreased compared with those in the parental cells. When H1993-MTA cells were treated with FGF2-targeting siRNA or anti-FGFR1 inhibitor, the increase of phosphorylation of ERK and AKT were induced. These data indicated the possibility that both FGF2 and TS could confer MTA resistance in the lung cancer cell lines in an independent manner, and that modification of signal transduction through FGF2-FGFR1 pathway might be involved in the development of MTA resistance in lung cancer cells. Citation Format: Kentaro Miura, Ken-ichi Ito, Takaaki Oba, Asumi Iesato. Fibroblast growth factor 2 (FGF2) is associated with the development of resistance to pemetrexed in lung cancer 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 4027.
Input-Output Analysis for Total Input Rate and Total Traced Mass of Body Cholesterol in Man
Authors: Williamperl, Paulsamuel
Journal: Circulation Research (1969)

The Stewart-Hamilton theorems for flow and volume are generalized to yield total input rate and total traced mass in multiple input, steady-state systems with partially labeled input. Application is made to existing decay curves of tracer cholesterol in human serum measured under a control steady state and again under a steady state of neomycin administration which lowered the serum cholesterol level. The effect of neomycin on the total traced mass of body cholesterol was to reduce it by 38, 40, 32, and 24 g, corresponding to 34, 40, 25, and 33%, in four patients studied. The present analysis utilizes only the area and the first time moment of the plasma decay curve. It is applicable to decay curves of more general shape than those that can be fitted by a small number of exponentials. The analysis does not require the assumption of compartments.
Abstract 15031: Apabetalone (RVX-208) Reduces Expression of Acute Phase Response Markers in vitro and in Patients With Cardiovascular Disease
Authors: Ewelina Kulikowski, Sylwia Wasiak, Dean Gilham, Cyrus Calosing, Laura Tsujikawa, Christopher Halliday, Mike Sweeney, Jan Johansson, Norm C Wong
Journal: Circulation (2016)

Introduction: Apabetalone (RVX-208) is an inhibitor of the epigenetic regulators bromodomain and extraterminal (BET) proteins, currently in a phase 3 outcomes trial in patients with cardiovascular ...
Abstract 11815: Prolonged Space Flight Induced Alterations in the Structure of Medaka Cardiac Muscle and Gene Expression
Authors: HirokazuEnomoto, NishantMittal, ShinjiMakino, KeiichiFukuda
Journal: Circulation (2015)

Introduction: Cardiovascular deconditioning (reduction of ventricular mass and blood pressure) induced by prolonged spaceflight. Little has been reported about histology and gene expression pattern of heart after long time in the international space station (ISS). The purpose of this study is to examine how microgravity affects the structure and gene expression of medaka cardiac muscle. Methods: Fifteen medaka fishes were sent to ISS. The fish lived in a space aquarium of ISS. Control medaka lived in same aquarium on the ground. After 2 weeks and 2 months of swimming in microgravity, medaka fish (N=5, each) were fixed in 4% paraformaldehyde at ISS. Cardiac morphology and structure were assessed by hematoxylin and eosin (HE), Azan and immuno-staining. The remaining 5 medaka fish, after 2 months at ISS, were treated by RNAlater for preservation of RNA for RT-PCR and RNA-Seq analysis. Results: The fishes at ISS were swimming in loops rather than straight line and tend to standstill. The body sizes were norma...
Cytotoxic and Proinflammatory CD8+ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice
Authors: TinKyaw, AmyWinship, ChristopherTay, PeterKanellakis, HamidHosseini, AnhCao, PriscillaLi, PeterTipping, AlexBobik, Ban-HockToh
Journal: Circulation (2013)

Background—Heart attacks and strokes, leading causes of deaths globally, arise from thrombotic occlusion of ruptured vulnerable atherosclerotic plaques characterized by abundant apoptosis, large necrotic cores derived from inefficient apoptotic cell clearance, thin fibrous caps, and focal inflammation. The genesis of apoptosis and necrotic cores in these vulnerable atherosclerotic plaques remains unknown. Cytotoxic CD8+ T lymphocytes represent up to 50% of leukocytes in advanced human plaques and dominate early immune responses in mouse lesions, yet their role in atherosclerosis also remains unresolved. Methods and Results—CD8+ T-lymphocyte depletion by CD8α or CD8β monoclonal antibody in apolipoprotein E-deficient mice fed a high-fat diet ameliorated atherosclerosis by reducing lipid and macrophage accumulation, apoptosis, necrotic cores, and monocyte chemoattractant protein 1, interleukin 1β, interferon γ, and vascular cell adhesion molecule 1. Transfer of CD8+ T cells into lymphocyte-deficient, apolipo...
Abstract 17722: Recipient Treatment With Donepezil, an Acetylcholinesterase Inhibitor , Abolishes Donor Heart Ischemia/Reperfusion Injury and Chronic Graft Failure Through TNF Inhibition in an Syngenic Rat Model
Authors: Xin Yuan, Xiao Teng, Jianfeng Hou
Journal: Circulation (2015)

Introduction: Ischemia/reperfusion injury (IRI) may have deleterious consequences for donor heart. The underlying mechanisms involve inflammation that may culminate in primary or chronic graft failure. Hypothesis: Donepezil, an acetylcholinesterase inhibitor, can protect the post-transplanted donor heart by inhibiting systemic inflammation of the recipients. Methods: Here, we report in Lewis to Lewis rat syngenic heart transplantation model that ischemia/reperfusion injury resulted in primary and chronic graft failure that was prevented by recipient treatment with peroral single-dose Donepezil. Results: Donepezil inhibited the release of cytokines (TNF, IL-1β, IL-6 and IL18), CD11b/18 positive cell infiltration and myocardial apoptosis in the recipient rats one week postoperatively. One month after transplantation, the graft survival rate in Donepezil group was 46.7% than that in SHAM group (P&lt;0.05); the EF value in Donepezil group was 13% higher than that in SHAM group (P&lt;0.05). The cardiac fibrosis grade was 1 grade lower in Donepezil group than that in SHAM group (P&lt;0.05). Methyllycaconitine blocked the actions of Donepezil, suggesting that the donor heart protection effects are α7-nAChRs-dependent. Conclusions: Our results reveal that recipient treatment with Donepezil protects donor hearts through TNF inhibition and TNF related downstream pathophysiological pathways. These results suggest a novel, clinically feasible strategy to protect donor hearts from IRI.
Abstract 648: Digital PCR in genetic diagnosis of NUT midline carcinoma
Authors: Shunsuke Okumura, Shin-ichi Chiba, Masatoshi Sado, Nana Takahashi, Takaaki Sasaki, Masahiro Kitada, Yoshinobu Ohsaki
Journal: Cancer Research (2018)

Abstract Background; NUT midline carcinoma (NMC) is a rare, highly aggressive tumor with t(15;19) translocation involving NUT midline carcinoma family member 1 (NUTM1) gene. NMC is genetically defined and diagnosed by RNA sequencing or by immunohistochemistry for NUT protein expression instead. However, it can be challenging to perform these assays on small biopsy specimens. We, here, report the utility of digital PCR (dPCR) assay for diagnosis of NMC. Methods; The QuantStudio 3D dPCR system (Thermo Fisher Scientific) was used. We designed optimal dPCR probes for the BRD4-NUT fusion gene and evaluated the dPCR method using NMC cell lines (HCC2429 and Ty82) and clinical samples. Total RNA was extracted from the cell lines and FFPE tissue samples from patients with thoracic tumors (RecoverAll total nucleic acid isolation kit, Thermo Fisher Scientific). cDNA was synthesized with SuperScript VILO cDNA kit (Thermo Fisher Scientific). PCR was performed using ProFlex PCR system (Thermo Fisher Scientific). Data was analyzed with QuantStudio 3D AnalysisSuite Cloud Software (Thermo Fisher Scientific). Results; We identified the BRD4-NUT fusion gene in HCC2429 and Ty82 cells using the dPCR system, which allowed us to detect the fusion gene at a prevalence &amp;lt; 0.1%. The fusion genes were detected in the clinical samples, and we successfully found NMC patients using the dPCR assay. Conclusion; We conclude the dPCR assay is an appropriate method for diagnosis of NMC. Citation Format: Shunsuke Okumura, Shin-ichi Chiba, Masatoshi Sado, Nana Takahashi, Takaaki Sasaki, Masahiro Kitada, Yoshinobu Ohsaki. Digital PCR in genetic diagnosis of NUT midline carcinoma [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 648.
Abstract 4909: Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib
Authors: Yingxue Chen, Martin Pass, Nuria Bui Bruna, Christine Stephens, Andrew Pierce, Wouter Hanekom, Hani Gabra, Helen Tomkinson, Nidal Al-Huniti
Journal: Cancer Research (2018)

Abstract Background: AZD0156 is a highly selective first oral ATM inhibitor in the clinic. Coordinating DNA single and double strand break repair, AZD0156 enhances the preclinical activity of olaparib, leading to its development as an antitumor agent in combination. We report here results from an ongoing phase 1 adaptive dose escalation study of AZD0156 in combination with olaparib. Methods: This phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of escalating doses of AZD0156 in combination with olaparib in patients with advanced malignancies. AZD0156 is mainly metabolized by CYP3A and FMO, which undergo genetic polymorphism. The flexible language incorporated in the protocol also allow rapid dose escalation beyond subtherapeutic doses. Results: PK data from the first 2 dose cohorts were lower than predicted and the AZD0156 dose was increased 4 X and dosing changed from QD (daily) to BD (twice daily). The mean terminal half-life of AZD0156 was 9-12 hours and PK was dose proportional. No significant drug-drug interactions (DDI) were observed with olaparib. Minor toxicities included nausea, vomiting and anemia in about 40% of patients in all cohorts. Grade 3 and 4 hematologic toxicities were observed in AZD0156 120mg BD with olaparib 200mg BD, and this dose level was considered intolerable. At doses of AZD0156 of 30 and 60mg BD, active target engagement was demonstrated. PK profile was similar across FMO genotype. Conclusion: Hematologic toxicities, consistent with the mode of action, emerged as dose-limiting toxicities of AZD0156 in combination with olaparib. Pharmacologically active doses of AZD0156 with olaparib were achieved more quickly in patients by using real-time PK, real-time genotyping, safety, DDI assessment, and PK/PD modelling. Citation Format: Yingxue Chen, Martin Pass, Nuria Bui Bruna, Christine Stephens, Andrew Pierce, Wouter Hanekom, Hani Gabra, Helen Tomkinson, Nidal Al-Huniti. Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib [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 4909.
Expression of bcl-2 Protein, an Inhibitor of Apoptosis, and Bax, an Accelerator of Apoptosis, in Ventricular Myocytes of Human Hearts With Myocardial Infarction
Authors: JunMisao, YukihiroHayakawa, MichiyaOhno, SatoshiKato, TakakoFujiwara, HisayoshiFujiwara
Journal: Circulation (1996)

Background In general, myocyte death in myocardial infarctions (MIs) is attributed to necrosis, but recently the involvement of apoptosis has been suggested. The ratio of bcl-2 protein, an inhibitor of apoptosis, to Bax protein, an inducer of apoptosis, determines survival or death after an apoptotic stimulus. We speculated that bcl-2 or Bax expression is induced by ischemia and that it may be related to myocyte death in human hearts. Methods and Results We studied immunohistochemically 37 autopsied human hearts (acute MI, n=15; old MI, n=12; normal hearts as a control, n=10) with the use of bcl-2 and Bax antibodies. There were no myocytes with positive bcl-2 immunoreactivity in the controls or hearts with old MI. However, myocytes with positive bcl-2 immunoreactivity were seen in 9 of 15 hearts (60%) with acute MI, in that it was localized only in salvaged areas surrounding the infarcted tissues. Myocytes with slightly positive Bax immunoreactivity were observed in the control hearts. In the salvaged myo...
Abstract 2142: High variability of TIGIT expression in Hodgkin's lymphoma
Authors: Ronald Simon, Niclas C. Blessin, Martina Kluth, Kristine Fischer, Claudia Hube-Magg, Wenchao Li, Georgia Makrypidi-Fraune, Björn Wellge, Tim Mandelkow, Nicolaus F. Debatin, Guido Sauter, Waldemar Wilczak, Andrea Hinsch
Journal: Cancer Research (2018)

Abstract Hodgkin's lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin lymphoma lymph nodes (n=40) and normal human tonsil (n=2) as a reference. The ME-TMA was stained with brightfield and multiplex fluorescence immunohistochemistry (IHC) in order to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD8, CD4, FOXP3) in the lymphocytic background. TIGIT and PD-1 expression was found in all (100%) analyzed HL samples. In general, TIGIT localized to the same cells as PD-1. IHC based identification of T cell subtypes revealed TIGIT and PD-1 expression on CD8+ cytotoxic T cells, CD4+ helper T cells and FOXP3+ regulatory T cells. Strikingly, expression levels of TIGIT and PD-1 were highly variable among the analyzed samples irrespective of the histological subtype of HL. Interestingly, highest levels of both proteins were found in one sample of nodular lymphocytic-predominant HL (NLPHL). The high variability of TIGIT and PD-1 expression was also independent from the T cell subtype. HL with high TIGIT/PD-1 expression on CD8 positive cells sometimes showed low TIGIT/PD-1 expression on CD4 or FOXP3 positive T cells and vice versa. However, the T cell subtypes differed with respect to the TIGIT:PD-1 ratio. In the majority of analyzed HL, FOXP3+ regulatory T cells expressed higher levels of TIGIT than of PD-1. This was different for CD8+ and CD4+ cells, where similar fractions of HL showed either more TIGIT as PD-1, or more PD-1 as TIGIT, or comparable levels of both receptors. In conclusion, TIGIT (and PD-1) expression is highly variable between patients with Hodgkin's lymphoma. TIGIT may play a particularly important role in FOXP3 regulatory T cells in the lymphocytic background. Citation Format: Ronald Simon, Niclas C. Blessin, Martina Kluth, Kristine Fischer, Claudia Hube-Magg, Wenchao Li, Georgia Makrypidi-Fraune, Björn Wellge, Tim Mandelkow, Nicolaus F. Debatin, Guido Sauter, Waldemar Wilczak, Andrea Hinsch. High variability of TIGIT expression in Hodgkin's 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 2142.
Addressing financial concerns of cancer clinical trial participants: Longitudinal outcomes of an equity intervention.
Authors: Ryan David Nipp, Hang Lee, Emily Gorton, Morgan Lichtenstein, Elyse R. Park, Bruce Allan Chabner, Beverly Moy
Journal: Journal of Clinical Oncology (2018)

6566 Background: Cancer patients’ (pts) financial concerns (FCs) represent a barrier to clinical trial (CT) participation and interventions targeting pts’ FCs are needed. We sought to assess the impact of an equity intervention on CT pts’ FCs. Methods: We developed an equity intervention to reimburse non-clinical expenses related to CTs (e.g. travel, lodging) for low income pts. From 7/2015-7/2017, we surveyed intervention and control pts matched by age, sex, cancer type, specific CT and CT phase. We longitudinally assessed pts’ FCs (cost concerns for CT-related travel and lodging), cost-coping strategies (e.g. altering medical care or lifestyle due to costs) and financial wellbeing (FWB; COST measure, scores range 0-44, higher scores = better FWB) at baseline, day 45 and day 90. We used longitudinal models to assess intervention effects over time. Results: We enrolled 260 pts (157 intervention, 103 controls); median age = 59.2 (range: 23.8-83.3); 66% female; 72% on phase I CTs. Intervention pts had lower incomes than controls (under $60k: 52% vs 24%, P < .001). At baseline, intervention pts were more likely than controls to report FCs for CT-related travel (41% vs 7%, P < .001) and lodging (33% vs 2%, P < .001). Intervention pts were more likely to report travel to appointments as their most significant FC (23% vs 7%, P = .001). Intervention pts were also more likely to report forgoing needed care (14% vs 1%, P = .001) and using savings to pay for care (84% vs 43%, P < .001). At baseline, intervention pts had worse FWB than controls (COST score: 15.3 vs 23.9, P < .001). Over time, intervention pts experienced greater improvements in their FCs about CT-related travel (-10% vs +1%, P = .02) and lodging (-4% vs +4%, P = .03) compared with controls. Intervention pts also reported travel to appointments as their most significant FC less often (+2% vs +11%, P = .08) and had improvements in their COST scores (+1.1 vs -0.3, P = .20), although these differences were not significant. Conclusions: This equity intervention improved CT pts’ FCs over time. Our findings highlight the substantial FCs of cancer CT pts, and underscore the need for interventions to address these concerns to improve access to CT participation for all pts with cancer.