tbuckley/cabot-search huggingface dataset:
Abstract 11534: HMG-CoA Reductase Inhibition Enhances Renoprotective Effects of Angiotensin Receptor1 Antagonism in Salt-Sensitive Hypertensive Rats
Authors: LinaHU, Xian WuCheng, ZheHuang, TakeshiSasaki, AikoInoue, HongxianWu, EnboZhu, MasafumiKuzuya, ToyoakiMurohara, KenjiOkumura
Journal: Circulation (2014)

Introduction: The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, improved renal dysfunction in patients with proteinuric kidney disease. Objective: We aimed to clarify the potential effect of a statin to enhance the inhibitory effect of an angiotensin type1 receptor blocker (ARB) on renal injury and the cellular mechanism of the effect of ARB on renal remodeling and proteinuria. Methods and Results: Dahl salt-sensitive (DS) rats on a high-salt diet were randomly assigned to four groups (n = 10 for each group) that were treated with either vehicle (0.5% carboxymethyl cellulose), a low or high dosage of olmesartan (1 or 3 mg/kg/d), or pitavastatin (1 mg/kg/d) plus olmesartan (1 mg/kg/d) from 12 to 19 weeks of age. Rats fed a low-salt diet served as age-matched controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis, and these changes were attenuat...
Abstract 4601: Dissecting the spatial heterogeneity of circulating tumor cells reveals CCL5-Treg-mediated immune evasion in hepatocellular carcinoma
Authors: Liang Wu, Miaomiao Jiang, Yunfan Sun, Xinrong Yang, Yong Hou, Jia Fan, Shiping Liu
Journal: Cancer Research (2018)

Abstract The prognosis of hepatocellular carcinoma (HCC) is closely linked to the occurrence of recurrent, metastatic disease. Metastasis has been proposed to be initiated by circulating tumor cells (CTCs); however, the transcriptomic plasticity and adaptive mechanisms of CTCs in systemic circulation are not well defined. Here, we established single-cell RNA-sequencing profiles of 113 CTCs isolated from four key vascular sites along the dissemination route in ten HCC patients. In our study, we found that single CTCs displayed profound spatial transcriptional heterogeneity within the circulatory system, which is associated with increased transcriptional activity, cell cycle progression, and chemokine-induced immune escape programs. In particular, CTCs dynamically drove chemokine (C-C motif) ligand 5 (CCL5) expression over the course of circulation. We demonstrated that increased CCL5 expression in turn recruited regulatory T cells to facilitate immune evasion and metastatic progression, as rigorously validated by our in vitro and in vivo models. Finally, we identified an inherently dormant CTC subset with an epithelial-mesenchymal transition and immune-evasive phenotype, and demonstrated its potential prognostic implications. Collectively, our results reveal the previously unappreciated spatial heterogeneity of CTCs, and define its role in diverse regulatory programs and cellular states. Our study offers new insight into metastatic mechanisms, highlighting the potential utility of anti-CTC therapeutic strategies. Citation Format: Liang Wu, Miaomiao Jiang, Yunfan Sun, Xinrong Yang, Yong Hou, Jia Fan, Shiping Liu. Dissecting the spatial heterogeneity of circulating tumor cells reveals CCL5-Treg-mediated immune evasion in hepatocellular 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 4601.
Abstract 2001: Transcriptional integrator p300 in human prostate tumor-initiating cells
Authors: Martina Gruber, Florian Handle, Zoran Culig
Journal: Cancer Research (2018)

Abstract Introduction p300 is a well-known coactivator of the androgen receptor (AR) and has been shown to play an important role in prostate cancer (PCa). The expression of p300 has been correlated to tumor volume and PCa progression. Therefore, we hypothesize that p300 may play an important role in tumor-initiating cells and therapy resistance. Due to its multifunctional role p300 may serve as a promising new therapeutic target for treatment of PCa. Ultimately, it is our aim to find new innovative therapeutic targets for castration resistant PCa. Material &amp; Methods The tumor-initiating capacity of the AR-negative PCa cell lines PC3 and Du145, as well as primary prostate epithelial cells was characterized by seeding a limiting number of cells per flask. Colony formation efficiency, colony type and detailed morphological information about each colony were determined by an automated pipeline that we have developed. Stable cell lines with doxycycline inducible p300 sh RNAs were generated by lentiviral transduction. Knockdown of p300 was verified by Western Blot and reduced p300 activity was confirmed by measuring histone h3 acetylation. Results In concordance with the literature we identified three colony types (holo-, mero- and paraclones) in PC3 and Du145 cell lines as well as primary PCa cells. Serial clonogenic assays confirmed in both cell lines that holoclones show the highest colony formation potential and maintain their tumor-initiating capacity over numerous rounds. In PC3 we detected 10% and in Du145 30% holoclones. Under optimal growth conditions p300 was detected in all colony types, however no differences in protein expression of p300 as well as on mRNA level were observed. Knockdown of p300 did not alter colony formation efficiency or the relative distribution of colony types. Conclusion Taken together, we confirmed the presence of tumor-initiating holoclones in PCa cell lines and primary prostate epithelial cells and established stable cell lines with inducible knockdown of p300. In contrast to several other types of malignancies, p300 has no specific role in regulation of stemness in our PCa models at the tested conditions. As a next step we will determine the effects of p300 knockdown during chemotherapy and radiation therapy to evaluate if p300 depletion may enhance the treatment efficacy and which role p300 plays in therapy resistance. Citation Format: Martina Gruber, Florian Handle, Zoran Culig. Transcriptional integrator p300 in human prostate tumor-initiating 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 2001.
Coronary and Systemic Hemodynamic Effects of Sustained Inhibition of Nitric Oxide Synthesis in Conscious Dogs
Authors: LouisPuybasset, Marie-LuceBéa, BijanGhaleh, Jean-FrançoisGiudicelli, AlainBerdeaux
Journal: Circulation Research (1996)

Sustained inhibition of NO synthesis (Nω-nitro-l-arginine [L-NNA], 20 mg·kg−1·d−1, 7 days) was investigated at rest and during exercise in conscious dogs. At rest, L-NNA did not alter mean arterial blood pressure but markedly increased total peripheral resistance (+ 73±14%, P<.01). Exaggerated hypertension was observed during exercise (+132±5 mm Hg after L-NNA versus +113±5 mm Hg before L-NNA, P<.01). L-NNA decreased the resting coronary artery diameter by 6±1% and suppressed its exercise-induced dilation but had no effect on coronary blood flow and resistance. L-NNA decreased flow repayment volumes during reactive hyperemia, but corresponding flow debt volumes remained unchanged. The cyclooxygenase inhibitor diclofenac (10 mg/kg) had no effect on reactive hyperemia parameters before L-NNA but reduced flow repayment volumes, durations, and corresponding debt-to-repayment ratios in L-NNA–treated dogs (all P<.05). In vitro, indomethacin blunted the residual relaxation to bradykinin of large coronary arterie...
Abstract 3629: Repeated abscopal effect with radiation and anti-PD-1 blockade in MMR deficient endometrial cancer
Authors: Michael S. Oh, Young Chae
Journal: Cancer Research (2018)

Abstract The combination of radiation therapy and immune checkpoint inhibitors has raised interest as possibly having synergistic antitumor effects. Radiation can induce both a local response as well as a systemic one that stimulates immune cells, which then can be further potentiated by immunotherapy. This abscopal effect has been validated in preclinical studies and is currently being studied in clinical trials, though it has yet to be reported in gynecologic cancers. A 64-year-old woman initially presented with vaginal bleeding and was subsequently diagnosed with stage IIIC endometrial adenocarcinoma with pelvic and para-aortic lymphadenopathy. She underwent surgical resection with adjuvant carboplatin and paclitaxel. Follow-up CT scans showed progression of disease, and over the next 18 months, the patient was sequentially treated with doxorubicin, topotecan, melphalan, docetaxel, and capecitabine. Analysis of a tumor biopsy demonstrated an MMR deficient phenotype with absent MLH1 and PMS2. Based on the recently-published data on the efficacy of PD-1 inhibitors in MMR deficient solid tumors, the patient was started on nivolumab. Meanwhile, she was given palliative radiation therapy to the following areas: painful cutaneous metastases on her left thigh; an L3 spinal metastasis; lymph nodes in the retroperitoneum, external iliacs, and left inguinal chain; and a symptomatic bladder mass. After radiation, the patient exhibited a strong partial response not only in the targeted lesions but also throughout her tumor burden, consistent with an abscopal effect. This response was sustained over many months and repeatable with each radiation session. The synergistic use of radiation therapy and immune checkpoint blockade may thus represent a powerful treatment modality in endometrial cancer and warrants further clinical investigation. Citation Format: Michael S. Oh, Young Chae. Repeated abscopal effect with radiation and anti-PD-1 blockade in MMR deficient endometrial 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 3629.
Abstract 4830: Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy
Authors: Eric Haines, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev
Journal: Cancer Research (2018)

Abstract M3814 is a selective inhibitor of DNA-PK in clinical development. It effectively blocks non-homologous end joining repair of DNA double strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By inhibiting DNA-PK catalytic activity in the presence of DSB damage, M3814 disrupts a previously unrecognized negative regulatory loop between DNA-PK and ATM, leading to increased activation of the ATM pathway, including its downstream targets, CHK2 and p53. As a result, in cancer cells expressing wild-type p53, DNA-PK inhibitor strongly activates the p53 response to DSB DNA damage and its two main functions- cell cycle arrest and apoptosis. While p53 activation in p53 wild-type epithelial cancer cells causes effective cell cycle arrest, the majority of the epithelial tumors lose their ability to undergo p53 dependent apoptosis. In contrast, tumor cells from patients with acute leukemia express wild-type p53 in with preserved p53 apoptotic function, making them amenable to p53 activation approaches. Here, we investigate the therapeutic potential of M3814 in combination with DSB-inducing agents in acute leukemia cells. M3814 strongly potentiated the activity of IR in three p53 wild-type leukemia cell lines (MOLM-13, MOLT-4, MV4-11) but had minimal effect on the p53-null HL-60 and THP-1 lines. This potentiation was due to enhanced activation of the p53 pathway as demonstrated by substantially increased expression of p53 transcriptional targets, p21 and PUMA, and induction of apoptosis only in p53 wild-type cells. M3814 showed synergism in p53-dependent cell killing with the topoisomerase inhibitors, daunorubicin and idarubicin, and 2-3 fold increase in the potency of daunorubicin/cytarabine combination in p53 wild-type acute myeloid leukemia (AML) cells. Daunorubicin/cytarabine/M3814 combinations were better tolerated by CD34+ bone marrow cells harvested from healthy volunteers and tested in vitro. These results support further exploration of M3814 as a novel combination partner in the treatment of p53 wild-type AML. Citation Format: Eric Haines, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy [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 4830.
Abstract 130: Cancer teammate survives longer: Role of cancer-associated a2 V-ATPase in regulation of neutrophil survival
Authors: Safaa A. Ibrahim, Arpita Kulshrestha, Gajendra K. Katara, Manoranjan Sahoo, Kenneth D. Beaman
Journal: Cancer Research (2018)

Abstract Tumor associated neutrophils (TAN) represent a significant portion of tumor leukocytes and accumulate in many types of cancer. TAN can survive for weeks in cancer tissues and have been proposed as key mediator of malignant transformation, tumor progression, angiogenesis and in the modulation of the antitumor immunity. Identifying cancer associated factors that promote the survival and protumorigenic properties of neutrophils will provide new targets for cancer therapy. Cancer cells secrete a peptide from the Nterminal domain of a2isoform vacuolar ATPase (a2NTD) that promotes the protumorigenic properties of neutrophils that enhances angiogenesis and tumor cell invasiveness. The present study attempts to decipher the role of a2NTD in the regulation of neutrophil apoptosis. The treatment of human neutrophils with recombinant a2NTD led to 2.1 fold increase in the percentage survival of neutrophils (P &amp;lt; 0.001). a2NTD treatment activates NF- kBp65 by activating reactive oxygen species (ROS) generation in neutrophils. Activation of NF- kB pathway leads to upregulation of the gene expression of anti-apoptotic factors; Bcl2-A1, Bcl-xL, c-Flip, G-CSF and downregulates the pro-apoptotic factors such as BAX. Parthenolide; NF-kB inhibitor, negated the effect of a2NTD on enhancing neutrophil survival confirming the involvement of NF-kB pathway in the a2NTD mediated increase of neutrophil survival. Further analysis showed that a2NTD treatment stabilizes the neutrophil mitochondrial membrane potential and decreases Bax translocation to the mitochondria that was associated with a decrease in caspase 9 and caspase 3 activity. Since there is a direct link between the intrinsic and the extrinsic pathways of apoptosis, our results showed that there was no change in the Fas and Fas ligand expression upon a2NTD treatment. Further analysis would uncover the effect of a2NTD treatment on the extrinsic pathway of apoptosis in neutrophils. Together, our results demonstrate a novel role of the cancer associated a2-vacuolar ATPase on retarding the mitochondrial death pathway in neutrophils by the action of a2NTD. Citation Format: Safaa A. Ibrahim, Arpita Kulshrestha, Gajendra K. Katara, Manoranjan Sahoo, Kenneth D. Beaman. Cancer teammate survives longer: Role of cancer-associated a2 V-ATPase in regulation of neutrophil survival [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 130.
Abstract 2005: CSCs induced from iPSCs indicate the trace of cancer cell culture conditioned media
Authors: Akimasa Seno, Tomonari Kasai, Heizo Tokutaka, Masaharu Seno
Journal: Cancer Research (2018)

Abstract Cancer stem cells (CSCs) show drug resistance and could be a source of cancer cells. Although these cells are recently considered more important than ever in cancer studies, the extremely small number of CSCs in actual cancer tissues makes the analysis difficult. Previously, we demonstrated that CSCs could be differentiated from induced pluripotent stem cells (iPSCs) in the presence of cancer cell conditioned media. We have confirmed the conditioned media from various types of cancer cell lines were successful to convert iPSCs into CSCs showing self-renewal property, differentiation potential, and tumorigenicity. To identify their differences between the generated CSCs, gene expression was compared by spherical self-organizing map (sSOM). Comparing with more than 1000 cells including stem cells, induced CSCs, CSCs obtained from cancer tissue or cancer cell line, and cancer cells or cancer tissues, known cancer stem cell markers were found not enough to classify CSCs. In the sSOM analysis, “ideal probe” (IP), which was supposed to characteristically be expressed in each group, was set to nomiate the marker gene. The distance close to the IP depicted some candidate marker genes in each group. The gene expression commonly shared among different types of CSCs was also searched. This IP revealed known cancer related gene Endthelin 1 as a commonly expressed gene. Moreover, when the CSCs were compared with the parental hiPSC and cancer cells, of which conditioned media was used for the conversion, sSOM showed that CSCs were not always differentiated towards their origin, but which genes should be responsible for generating CSCs. These results indicate that the induced CSCs should be the initial state of cancer cells and imply some important role of Endothelin 1 in CSC development. Citation Format: Akimasa Seno, Tomonari Kasai, Heizo Tokutaka, Masaharu Seno. CSCs induced from iPSCs indicate the trace of cancer cell culture conditioned media [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 2005.
Abstract 17712: Comparison of Three-Dimensional and Two-Dimensional Quantitative Coronary Angiography and Intravascular Ultrasound for the Functional Assessment of Coronary Lesions
Authors: TakeshiNishi, TakashiNakayama, YoshihideFujimoto, YoshioKobayashi
Journal: Circulation (2014)

Introduction: Three-dimensional (3-D) quantitative coronary angiography (QCA) reportedly allows a more accurate depiction of true vessel geometry when compared with standard two-dimensional (2-D) QCA and has been validated by intravascular ultrasound (IVUS). Although IVUS is currently thought to provide the most accurate measurements of vessel geometry and lesion severity, 3-D QCA measurements can be performed on existing standard coronary angiography images without the need for additional time or equipment during the procedure. Hypothesis: We assessed the hypothesis that 3-D QCA measurements and IVUS are comparable in accuracy in predicting physiologically significant stenosis assessed by fractional flow reserve (FFR). Methods: Forty lesions in 38 patients were assessed by FFR, IVUS, and 2-D and 3-D QCA. Correlations between anatomical data and FFR were analyzed. The area under the receiver-operating characteristic (ROC) curve (AUC) was calculated to identify the accuracy of predicting FFR ≤0.80. Results...
Abstract 12864: Impact of Calcification Severity on Clinical Outcomes Following Endovascular Therapy in the Patients With Peripheral Artery Disease Presenting With Superficial Femoral Artery Lesions
Authors: Shota Okuno, Masashi Fujita, Osamu Iida, Masaharu Masuda, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takashi Kanda, Tatsuya Shiraki, Akihiro Sunaga, Takuya Tsujimura, Yasuhiro Matsuda, Koji Yanaka, Takuya Ohashi, Masaaki Uematsu
Journal: Circulation (2015)

Background: Although vessel calcification results in poor clinical outcomes following endovascular therapy (EVT) in patients with peripheral artery disease (PAD), the Impact of calcification severity on clinical outcomes remains unclear. Methods: A total of 394 consecutive patients (mean age 72.4±8.3 years; 74 % male) with PAD who underwent EVT for de novo superficial femoral artery lesions in our hospital from January 2010 to December 2013 were retrospectively analyzed. These patients were stratified into three groups by fluoroscopy and digital subtraction angiography in the AP projection (no calcium group: no visible calcium at the lesion, unilateral group: unilateral calcification at the lesion, bilateral group: bilateral calcification at the lesion). The primary outcome measure was primary patency, while the secondary outcomes were survival and major adverse limb event (MALE). Cox proportional hazard analysis was performed to explore if this classification was an independent predictor of primary patency. Results: 224 (57 %) patients had diabetes, 83 (21 %) were on hemodialysis. Prevalence of TASC C/D was 50% (199 of 394) and prevalence of three groups; no calcium, unilateral and bilateral, was 55% (214 of 394), 28% (110 of 394), 17% (70 of 394), respectively. Mean lesion length and reference vessel diameter at the treated segment was 152.1±95.7 mm and 5.7±0.9 mm. Primary patency at 2 year was 70.0% in no calcium group, 68.9% in unilateral group, and 45.8% in bilateral group, respectively; survival rate at 2 year was 96.4% in no calcium group, 94.6% in unilateral group, and 87.4% in bilateral group, respectively; MALE at 2 year was 1.3% in no calcium group, 4.0% in unilateral group, 8.2% in bilateral group, respectively. Bilateral calcification was an independent predictor of primary patency, as were lesion length, lesion diameter and stent use. Conclusions: Bilateral calcification was independently associated with primary patency, MALE and survival after EVT.
Abstract 775: HIPStA, a high-throughput alternative to CETSA®
Authors: Kelvin F. Cho, Christopher Rose, Taylur Ma, Donald Kirkpatrick, Robert A. Blake
Journal: Cancer Research (2018)

Abstract The measurement of drug - target interaction in the cellular context is critical to many drug development programs. The Cellular Thermal Stability Assay (CETSA®) represents an established broadly applicable method for measuring drug target interaction. However, in its classic format, it has some limitations that make it difficult to scale to the throughput typically required for a drug development project. It requires heating samples to different temperatures and centrifugation and / or filtration steps which limit throughput. The HSP90 Inhibitor Protein Stability Assay (HIPStA) is a novel method for measuring drug target interaction. Like CETSA®, HIPStA is based on the premise that the binding of a ligand to a target protein can influence that protein's stability. Instead of using heat to destabilize a protein, HIPStA uses a Heat Shock Protein 90 inhibitor (HSP90i) to cause protein instability. Instead of scanning a range of different temperatures to establish a thermal denaturation curve, HIPStA applies a range of concentrations of an HSP90i to determine an HSP90i induced denaturation curve, and ultimately measures the ability of a compound to stabilize a protein. We present data demonstrating the proof of concept for the HIPStA method, using 3 different classes of drug discovery targets: Receptor tyrosine kinases, Nuclear Hormone Receptors and Cytoplasmic Protein Kinases. HIPStA represents a scale-able method for detecting drug-target interaction in cells. Citation Format: Kelvin F. Cho, Christopher Rose, Taylur Ma, Donald Kirkpatrick, Robert A. Blake. HIPStA, a high-throughput alternative to CETSA® [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 775.