tbuckley/cabot-search huggingface dataset:
Abstract 16039: CX3CR1 And CCR2 Synergistically Modulate Inflammatory but Not Metabolic Effects of High-fat Feeding
Authors: Hanrui Zhang, Christine C Hinkle, Sean O’Neill, Jennifer Caughey, Emma Lynch, Gina Lynch, Rachana Shah, Rexford S Ahima, Muredach P Reilly
Journal: Circulation (2015)

Introduction: Obesity is associated with a systemic inflammatory reaction that has been associated with the development of type 2 diabetes and atherosclerosis. Substantial evidence points towards the C-C motif chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) as important modulators of metabolic and inflammatory phenotypes in high fat diet (HFD)-induced obesity, but the synergistic effects of dual targeting of CX3CR1 and CCR2 have not been studied. Hypothesis: CX3CR1 and CCR2 exert synergistic effects in HFD-induced obesity. Methods: C57BL/6J wild type mice (WT), Cx3cr1 -/- , Ccr2 -/- and Cx3cr1 -/- Ccr2 -/- double knockout mice were fed a 45% HFD (D124551, Research Diets), which is known to promote hypertriglyceridemia and insulin resistance, for up to 6 months starting at 12-wks old (n=10-16 male mice per group). Results: WT, Cx3cr1 -/- , Ccr2 -/- , and Cx3cr1 -/- Ccr2 -/- gained weight at a similar rate and developed similar degrees of adiposity and hyperglycemia in response to 45% HFD. All groups demonstrated progressive impairment in glucose tolerance, insulin sensitivity (by Insulin Tolerance Test), and glucose-evoked insulin secretion. A complete blood cell count with differential suggested reduced monocyte count in Ccr2 -/- (22.2 ± 10.1 % of WT, mean±SEM, P&lt;0.05) and Cx3cr1 -/- Ccr2 -/- (10.6 ± 1.9% of WT, P&lt;0.05), but not in Cx3cr1 -/- (82.8 ± 16.3 % of WT, P=0.45), consistent with the impaired monocytosis due to Ccr2 deficiency. FACS analysis showed that in stromal vascular cells from epididymal adipose, % of CD45(+)F4/80(+)CD11c(+)MGL1(-) M1-like macrophage was lower while CD45(+)F4/80(+)MGL1(+)CD11c(-) M2-like macrophage was higher in the Cx3cr1 -/- Ccr2 -/- mice vs. WT mice. In contrast, a single knockout of Cx3cr1 or Ccr2 did not affect macrophage phenotypic switching. Conclusion: A single knockout or double knockout of Cx3cr1 and Ccr2 did not affect weight gain, glucose levels and insulin sensitivity in response to HFD. However, the Cx3cr1 -/- Ccr2 -/- but not the single knockout of Cx3cr1 or Ccr2 mice, showed reduced adipose macrophage activation. The results indicate that CX3CR1 and CCR2 synergistically modulate inflammatory but not metabolic effects of HFD.
Abstract LB-360: JNKs-mediated phosphorylation of human stromal xbp1s regulates multiple myeloma growth &amp; osteolysis
Authors: Risheng Chen, Guoshuang Xu, Wissam Beaino, Kai Lui, Xuemei Zeng, Nathan Yates, Rong Chong, Konstas Verdelis, G. David Roodman, Denise Toscani, Nicola Giuliani, Yan Lin, Carolyn J. Anderson, Hongjiao Ouyang
Journal: Cancer Research (2018)

Abstract Spliced X-box binding protein-1 (XBP1s) is a major effector of the unfolded protein response (UPR) signaling. We previously reported that human XBP1s in bone marrow stromal cells plays an essential role in regulating stromal support of multiple myeloma bone disease (MMBD). Here we report that human XBP1s (hXBP1s) is a physiological &amp; direct phosphorylation substrate of JNKs. This phosphorylation greatly increases hXBP1s protein degradation by the E3 ubiquitin ligase β-TrCP. Mutation of the phosphorylation site of JNKs to alanine largely prevents JNK phosphorylation of XBP1s &amp; JNK-induced protein degradation of hXBP1s. Further, we found that bone marrow stromal cells (BMSCs) harboring this XBP1s mutant are resistant to JNK phosphorylation and provided significantly greater support of MM growth and MM-induced bone destruction both in vitro &amp; in vivo, compared with counterparts expressing WT hXBP1s. Finally, we observed that JNK-mediated phosphorylation of hXBP1s is associated with favorable therapeutic responses of MM patients to combination therapy of bortezomib, &amp;/or dexamethasone &amp;/or thalidomide, MM drugs known to stimulate JNK. These results suggest p-hXBP1sJNK is a potential predictive biomarker for MM patients' response to the drug treatment. Taken together, our study provides the first evidence that hXBP1s is a novel physiological &amp; direct target of JNK phosphorylation and demonstrates the pathophysiological significance of this event in the hXBP1s-mediated bone microenvironment support of MM growth and MM-induced bone destruction. Citation Format: Risheng Chen, Guoshuang Xu, Wissam Beaino, Kai Lui, Xuemei Zeng, Nathan Yates, Rong Chong, Konstas Verdelis, G. David Roodman, Denise Toscani, Nicola Giuliani, Yan Lin, Carolyn J. Anderson, Hongjiao Ouyang. JNKs-mediated phosphorylation of human stromal xbp1s regulates multiple myeloma growth &amp; osteolysis [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 LB-360.
Abstract 15036: Papillary Muscle Sling and Mitral Valve Repair for Secondary Mitral Regurgitation: The SLING Study
Authors: Christos G Mihos, Romain Capoulade, Evin Yucel, Serguei Melnitchouk, Judy Hung
Journal: Circulation (2016)

Background: There is a 30-60% incidence of recurrent mitral regurgitation after mitral valve annuloplasty (Ring) for secondary mitral regurgitation (MR). A concomitant papillary muscle sling (Ring+...
Abstract 5663: Proteomic analysis of exosomes isolated from ccRCC cell lines
Authors: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Kengo Horie, Masafumi Ito, Takashi Deguchi
Journal: Cancer Research (2018)

Abstract Purposes of the study: Clear renal cell carcinoma (ccRCC) is one of the most lethal malignant tumors. Molecular targeted therapies have been used to improve outcomes for metastatic or advanced ccRCC. However, currently approved therapies have limited success and a cure remains elusive. Since ccRCC could be curable if diagnosed at the early stage, novel diagnostic approach is needed to identify circulating markers that may help diagnose early and evaluate prognosis. Exosomes are membrane vesicles with a diameter of 40-150 nm that are secreted by various types of cells including cancer cells. Exosomes contain a variety of molecular constituents of their origin such as proteins and nucleic acids. Over the years, exosome has been suggested to be a novel diagnostic marker. The purpose of this study is to find candidates of ccRCC markers in exosomes. Experimental procedures: Exosomes were collected from cell culture supernatant of RPTEC human renal proximal tubule epithelial cells and ccRCC cell lines (Caki-1, KMRC-1, and OS-RC-2) by ultracentrifugation. Isolation of exosome was confirmed by western blot analysis for CD9. Exosome fraction was analyzed by iTRAQ-based quantitative proteomics. Results: A total of 52 proteins were detected and 3 proteins were found to be upregulated by more than 1.2 fold in exosomes isolated from ccRCC cells compared with those from RPTEC cells. Twelve proteins were found to be downregulated by less than 0.8 fold in exosomes from ccRCC cells compared with those from RPTEC cells. The expression profiles of several proteins were verified by western blot analysis. Conclusions: While major challenges still remain, exosome studies in ccRCC could provide a wealth of information to find novel diagnostic and prognostic markers. Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Kengo Horie, Masafumi Ito, Takashi Deguchi. Proteomic analysis of exosomes isolated from ccRCC cell lines [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 5663.
A Myosin Missense Mutation, Not A Null Allele, Causes Familial Hypertrophic Cardiomyopathy
Authors: HirofumiNishi, AkinoriKimura, HaruhitoHarada, YoshinoriKoga, KyoAdachi, KohmeiMatsuyama, TakeshiKoyanagi, SeikohYasunaga, TsutomuImaizumi, HironoriToshima, TakehikoSasazuki
Journal: Circulation (1995)

Background Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac β–myosin-heavy-chain (β-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac β-MHC gene, ie, an α/β hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood. Methods and Results We analyzed the structure of the cardiac β-MHC gene from patients with HCM by using polymerase chain reaction–DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined ...
Abstract 1651: In vitro and in vivo profile of the preclinical candidate and MPS1 kinase inhibitor CCT289346
Authors: Hannah Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Amir Faisal, Grace W. Mak, Angela Hayes, Lisa O'Fee, Harry Saville, Alexis De Haven Brandon, Jennie Roberts, Gary Box, Melanie Valenti, Alan T. Heneley, Katie Walsh, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Rob L. van Montfort, Julian Blagg, Spiros Linardopoulos, Swen Hoelder
Journal: Cancer Research (2018)

Abstract The mitotic kinase MPS1 (also known as TTK) is one of the main components of the spindle assembly checkpoint. MPS1 is required for chromosome alignment and kinetochore-microtubule error correction. Cancer cells are dependent on MPS1 to cope with chromosomal instability resulting from aberrant numbers of chromosomes. Moreover, MPS1 has been found to be deregulated in a large number of tumor types. MPS1 kinase inhibitors induce cancer cells to prematurely exit mitosis with incorrectly attached and unaligned chromosomes, causing severe chromosome mis-segregation, aneuploidy and cell death. These data stimulated us to pursue MPS1 as a cancer target. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, such as paclitaxel. Here we disclose CCT289346, an MPS1 inhibitor currently completing late stage preclinical development. We describe the final stages of chemical optimisation and the data driven selection and nomination of CCT289346 as our preclinical candidate. We report key in vitro and in vivo preclinical data such as kinase profiling, PK in mouse, rat and dog, PK/PD relationship and efficacy in different in vivo models. Citation Format: Hannah Woodward, Paolo Innocenti, Kwai-Ming J. Cheung, Sébastien Naud, Amir Faisal, Grace W. Mak, Angela Hayes, Lisa O'Fee, Harry Saville, Alexis De Haven Brandon, Jennie Roberts, Gary Box, Melanie Valenti, Alan T. Heneley, Katie Walsh, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Rob L. van Montfort, Julian Blagg, Spiros Linardopoulos, Swen Hoelder. In vitro and in vivo profile of the preclinical candidate and MPS1 kinase inhibitor CCT289346 [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 1651.
Abstract 2229: Mammography assessment of microcalcifications using a pixel detector system
Authors: Carlos Ávila Bernal, Gerardo Roque, Roberto Rueda, Jorge Racedo
Journal: Cancer Research (2018)

Abstract Breast cancer is a major public health problem being the most frequently diagnosed malignancy and the second leading cause of dead from cancer among women in the United States. In 2015, there were expected around 231,840 new cases of invasive breast cancer, as well as 60,290 cases of in situ breast cancer, and 40,290 deaths. Worldwide, it represents 23% of the total cases diagnosed of cancer and 14% of the cancer deaths in female. Diagnosing breast cancer before it has the potential to invade surrounding tissue and metastasize can increase the chance of survival, reduce poor prognosis and the need of aggressive treatment. This is one of the main goals of early diagnosis that advocates mammography, the clinical examination and the breast self-examination as screening modalities for breast cancer. Recently, other technologies have been proposed like ultrasound and magnetic resonance imaging (MRI). Although these screening methods have reduced the relative risk of death, they have some limitations in some population groups. The aim of this work is adapting and testing a semiconductor pixel detector, Timepix in a custom-swine breast phantom to evaluate its technical feasibility to introduce this technology in a clinical setting for mammography assessment based on microcalcification detection. Swine model is commonly used in medical research based on anatomical and histopathological characteristics closely resemble those of humans, and this is an advantage over the wax-based phantoms that contains aluminum oxide (Al2O3) specks, nylon fibers and other inclusions to mimic microcalcifications and histopathological structures. The Timepix detector was used together with a Tungsten microfocus X-ray to detect hydroxyapatite crystals mimicking malignant microcalcifications with sizes ranged between 153-827μm, embedded into the swine phantom. To compare the detection performance in the swine phantom, a commercial phantom has been used (Model 015 CIRS Inc., Norfolk, VA, US). Both phantoms were tested on a clinical mammography system (Selenia Dimensions AWS 5000 ET19) and by using the experimental setup with the Timepix. This approach has potential to be used for mammography screening in different population groups based on its performance in microcalcifications detection. The results are highly relevant for further studies of the feasibility of pixel detectors for risk assessment and early diagnosis of breast cancer. Citation Format: Carlos Ávila Bernal, Gerardo Roque, Roberto Rueda, Jorge Racedo. Mammography assessment of microcalcifications using a pixel detector system [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 2229.
Abstract 3443: Full-length characterization of transcript isoforms to investigate cancer-associated mutations
Authors: Alison Tang
Journal: Cancer Research (2018)

Abstract Mutations in the splicing factor SF3B1 in various cancers have been associated with characteristic alterations in splicing. SF3B1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and is associated with poor patient prognosis. While alternative splicing patterns caused by mutations in SF3B1 on a junction level have been observed, these patterns have not been systematically examined on an isoform level. Isoform-level analyses are imperative for building a better understanding of altered splicing in a cell; exon connectivity is best resolved using long reads. As such, we have resequenced cDNA from CLL samples with and without K700E mutation in SF3B1, as well as a normal B cell, with nanopore sequencing technology. By converting changes in current caused by blockage of DNA threading through a nanopore into sequence, nanopore sequencing can sequence complete molecules of DNA that exceed 200kb in length. We have developed a novel workflow to perform isoform-level differential splicing analyses leveraging the full-length transcript data that nanopore affords. We report results from nanopore sequencing data that are concordant with known SF3B1 biology from short read sequencing as well as altered splicing patterns that are only observed definitively using long reads. Splicing analysis of nanopore reads between the SF3B1WT and SF3B1K700E identifies a bias toward increased alternative 3' splice sites than alternative 5'. In addition, we observe a relative decrease in the expression of genes with intron retention events in CLL samples compared to B cell. We also discover a previously unreported finding of enrichment in intron retention events in SF3B1WT relative to SF3B1K700E and no enrichment between CLL SF3B1MT and B cell, suggesting that mutated SF3B1 in CLL modifies the intron retention landscape to be more similar to a normal phenotype. Gene ontology analyses reveal enrichment in nuclear export in genes associated with intron retention events, and we postulate that many of these are detained introns of transcripts that are kept in the nucleus. With full-length cDNA sequence, we are also able to better detect premature termination codons and estimate the proportion of transcripts subject to nonsense-mediated mRNA decay. As nanopore sequencing has yet to become a routine tool for characterization of the transcriptome, our work demonstrates the utility of nanopore sequencing for cancer and splicing research. Citation Format: Alison Tang. Full-length characterization of transcript isoforms to investigate cancer-associated mutations [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 3443.
Abstract 1107: Cell-surface vimentin-positive macrophages like CTCs as novel biomarkers of metastatic gastrointestinal stromal tumors
Authors: Heming Li, Qing H. Meng, Hyangsoon Noh, Neeta Somaiah, Keila E. Torres, Xueqing Xia, Izhar Singh Batth, Cissimol P. Joseph, Zachary A. Mulder, Ruoyu Wang, Shulin Li
Journal: Cancer Research (2018)

Abstract Background: Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal tract sarcomas and are heavily infiltrated with tumor-associated macrophages (TAMs). Biomarkers specifically capturing circulating tumor cells (CTCs) that can be used to noninvasively determine the disease status in GIST patients have been lacking. Patients and Methods: To fill this gap, we captured both regular CTCs and TAMs from GIST patients' blood and tumor samples using our proprietary cell-surface vimentin (CSV) antibody 84-1 and the TAM markers CD14 and CD68 based on our previous established CTC detection method from 104 localized or metastatic sarcoma patients and 10 healthy donors. Also, freshly procured metastatic GIST tissues were obtained from four patients. Results: We defined a rare population of CSV+ macrophage-like CTCs (ML-CTCs) in metastatic GIST patients' blood samples with expression of CD14 and CD68 but not CD45. Also, we demonstrated CSV+ ML-CTCs to be tumor microenvironment-derived. Metastatic GIST patients had markedly higher numbers of CSV+ ML-CTCs than localized GIST patients and healthy blood donors. However, regular CTC counts could not predict metastasis of GISTs but could for other types of sarcoma. Notably, CSV+ ML-CTCs were represented as M1-like macrophages in their phenotype and function. Conclusions: CSV+ ML-CTCs are novel biomarkers for prediction of metastatic risk and therapeutic response in GIST patients. Routinely monitoring these cells will be an important approach to liquid biopsy analysis of GISTs. Citation Format: Heming Li, Qing H. Meng, Hyangsoon Noh, Neeta Somaiah, Keila E. Torres, Xueqing Xia, Izhar Singh Batth, Cissimol P. Joseph, Zachary A. Mulder, Ruoyu Wang, Shulin Li. Cell-surface vimentin-positive macrophages like CTCs as novel biomarkers of metastatic gastrointestinal stromal tumors [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 1107.
Initial Experience With Remote Catheter Ablation Using a Novel Magnetic Navigation System
Authors: SabineErnst, FeifanOuyang, ChristianLinder, KlausHertting, FabianStahl, JulianChun, HitoshiHachiya, DietmarBänsch, MatthiasAntz, Karl-HeinzKuck
Journal: Circulation (2004)

Background— Catheters are typically stiff and incorporate a pull-wire mechanism to allow tip deflection. While standing at the patient’s side, the operator manually navigates the catheter in the heart using fluoroscopic guidance. Methods and Results— A total of 42 patients (32 female; mean age, 55±15 years) underwent ablation of common-type (slow/fast) or uncommon-type (slow/slow) atrioventricular nodal reentrant tachycardia (AVNRT) with the use of the magnetic navigation system Niobe (Stereotaxis, Inc). It consists of 2 computer-controlled permanent magnets located on opposite sides of the patient, which create a steerable external magnetic field (0.08 T). A small magnet embedded in the catheter tip causes the catheter to align and to be steered by the external magnetic field. A motor drive advances or retracts the catheter, enabling complete remote navigation. Radiofrequency current was applied with the use of a remote-controlled 4-mm, solid-tip, magnetic navigation–enabled catheter (55°C, maximum 40 W,...
Statins Protect Human Aortic Smooth Muscle Cells From Inorganic Phosphate-Induced Calcification by Restoring Gas6-Axl Survival Pathway
Authors: Bo-KyungSon, KoichiKozaki, KatsuyaIijima, MasatoEto, TaroKojima, HidetakaOta, YukaSenda, KojiMaemura, ToruNakano, MasahiroAkishita, YasuyoshiOuchi
Journal: Circulation Research (2006)

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K–dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 μmol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which w...
Abstract 15367: Optimal Gait Speed Cut-off Values According to Age and Gender in Predicting Cardiovascular Events in Patients after Acute Myocardial Infarction
Authors: ChikaKawashima, YasushiMatsuzawa, HiroyukiSuzuki, EiichiAkiyama, NobuhikoMaejima, NoriakiIwahashi, KengoTsukahara, KiyoshiHibi, MasamiKosuge, ToshiakiEbina, SatoshiUmemura, KazuoKimura
Journal: Circulation (2014)

Background: Gait speed is a simple marker of frailty, and is inversely related to cardiovascular mortality among the elderly. In addition, we previously reported the association of slow gait speed with increased risk of cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI). Since gait speed is strongly related to gender and age, we sought to assess prognostic utility of gait speed and to determine its optimal cut-off values according to gender and age to predict subsequent cardiovascular events in patients with STEMI. Methods: We undertook a prospective observational study of gait speed in 472 patients with successful reperfusion therapy within 12 hours of STEMI onset. Gait speeds were measured during 200-meter walk before discharge, and all patients were followed for cardiovascular events which consist of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Optimal cut-off values of gait speed were defined using Youden index, according to gender ...