tbuckley/cabot-search huggingface dataset:
Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol Versus Standard Dual Antiplatelet in Patients With High Posttreatment Platelet Reactivity
Authors: Yi-Da Tang, Wenyao Wang, Min Yang, Kuo Zhang, Jing Chen, Shubin Qiao, Hongbing Yan, Yongjian Wu, Xiaohong Huang, Bo Xu, Runlin Gao, Yuejin Yang, Xun Yuan, Hongwen Ji, Zhou Zhou, Zhaohui Liu, Jue Chen, Jinqing Yuan, Haibo Liu, Jie Qian, Fenghuan Hu, Chunli Shao, Hanjun Zhao, Yihong Hua, Jie Lu
Journal: Circulation (2018)

Patients undergoing percutaneous coronary intervention react differently to antiplatelet drugs. Those with low responsiveness to clopidogrel have a higher risk of cardiac ischemic events. The goal of this study is to conduct a head-to-head comparison of the safety and effectiveness of intensified antiplatelet therapies (either double-dose clopidogrel [DOUBLE] or adjunctive cilostazol [TRIPLE]) and conventional strategy (STANDARD) in patients after percutaneous coronary intervention.In this single-center, randomized, controlled trial, we used thromboelastography, a platelet function test, to select 1078 patients undergoing percutaneous coronary intervention at high thrombotic risk and compared the intensified antiplatelet therapies with standard antiplatelet therapy. The primary outcome was the incidence of major adverse cardiac and cerebrovascular events at 18 months after percutaneous coronary intervention, defined as a composite of all-cause death, myocardial infarction, target vessel revascularization, or stroke. Bleeding Academic Research Consortium defined bleeding complications (types 1, 2, 3, or 5) were the safety end points.The primary end point occurred in 52 patients (14.4%) in the STANDARD group, 38 patients (10.6%) in the DOUBLE group, and 30 patients (8.5%) in the TRIPLE group (hazard ratio, 0.720; 95% confidence interval, 0.474-1.094, DOUBLE versus STANDARD; hazard ratio, 0.550; 95% confidence interval, 0.349-0.866, TRIPLE versus STANDARD). No significant difference in the rates of major bleeding (Bleeding Academic Research Consortium grade≥3) was found in the DOUBLE group (3.34% versus 1.93% in STANDARD, P=0.133) and the TRIPLE group (2.53% versus 1.93% in STANDARD, P=0.240). The rate of Bleeding Academic Research Consortium-defined minor bleeding increased in the DOUBLE group (27.4% versus 20.3% in STANDARD, P=0.031), but not in the TRIPLE group (23.6% versus 20.3% in STANDARD, P=0.146).In patients with low responsiveness to clopidogrel, as measured by thromboelastography, the intensified antiplatelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding. Decreased trend of negative outcomes could be observed in patients with double dosage of clopidogrel, but the difference was not significant.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01779401.
Abstract 574:BRAFV600Emutation and loss of CDX2 synergize in serrated colorectal tumorigenesis
Authors: Naoya Sakamoto, Ying Feng, Takuya Hattori, Masayuki Shimoda, Akira Ishikawa, Ririno Honma, Takao Hinoi, Hiroyuki Egi, Hideki Ohdan, Yasunori Okada, Eric Fearon, Wataru Yasui
Journal: Cancer Research (2018)

Abstract While many CRCs arise from adenomatous polyps through what we call “adenoma-carcinoma sequence,” it has been estimated that up to 20% of CRCs likely evolve from an alternative pathway, so-called ‘‘serrated pathway.' However, only 8-10% of CRCs display definitive serrated morphology at diagnosis. We previously examined expression of differentiation and molecular markers that are most likely to be involved in serrated tumor development by using 36 serrated CRCs and found CDX2 loss or BRAF mutations often together. We then generated a mouse model that can be induced concurrent biallelic inactivation of Cdx2 (Cdx2-/-) and expression of mutant BRAFV600E in adult mouse colon epithelium, and the Cdx2-/-/BrafV600E tumors showed a quite similar phenotype to that of CDX2-negative serrated CRCs. Through the validation of global gene expression profile including the mouse models and human CRCs, we focused on ADAM28 as a candidate because ADAM28 was significantly upregulated in Cdx2-/-/BrafV600E tumor and CRCs with low CDX2 expression and BRAFV600E mutation. We examined ADAM28 expression using 12 CRC cases with BRAFV600E mutation (8 of 12 displayed serrated feature) and 12 CRC cases with KRAS codon 12/13 mutation and found that ADAM28 was specifically upregulated in BRAF mutant CRC cases. Among 10 CRC cell lines (DLD-1, Lovo, SW48, SW480, SW837, SW1116, Caco2, RKO, HT-29, HCT-116), only HT-29, which has many phenotypic and genetic similarities to serrated CRC, showed a robust expression of membranous type ADAM28, and 9 of 10 CRC cells, except for RKO, showed weak to modest expression of active-form ADAM28. Further in-depth studies are ongoing to clarify the solid evidences, especially the utility of ADAM28 as a diagnostic marker for serrated CRCs and the direct effect of ADAM28 onto cell growth of CRC cells using ADAM28-specific antibody. We present a novel transgenic model of human serrated CRC to highlight the suitability of centering on CDX2 loss and BRAFV600E in the pathogenesis. This model has a great potential to figure out the mechanisms underlying in serrated tumor progression and identify the candidates of new biomarkers and therapeutic targets of CRCs with serrated morphology. Citation Format: Naoya Sakamoto, Ying Feng, Takuya Hattori, Masayuki Shimoda, Akira Ishikawa, Ririno Honma, Takao Hinoi, Hiroyuki Egi, Hideki Ohdan, Yasunori Okada, Eric Fearon, Wataru Yasui. BRAFV600E mutation and loss of CDX2 synergize in serrated colorectal tumorigenesis [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 574.
Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing
Authors: Hermela Shimelis, Holly LaDuca, Chunling Hu, Steven N Hart, Jie Na, Abigail Thomas, Margaret Akinhanmi, Raymond M Moore, Hiltrud Brauch, Angela Cox, Diana M Eccles, Amanda Ewart-Toland, Peter A Fasching, Florentia Fostira, Judy Garber, Andrew K Godwin, Irene Konstantopoulou, Heli Nevanlinna, Priyanka Sharma, Drakoulis Yannoukakos, Song Yao, Bing-Jian Feng, Brigette Tippin Davis, Jenna Lilyquist, Tina Pesaran, David E Goldgar, Eric C Polley, Jill S Dolinsky, Fergus J Couch
Journal: JNCI Journal of the National Cancer Institute (2018)

Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor–negative, progesterone receptor–negative, human epidermal growth factor receptor–negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.
Parvalbumin-Interneuron Output Synapses Show Spike-Timing-Dependent Plasticity that Contributes to Auditory Map Remodeling
Authors: Evan D. Vickers, Christopher Clark, Denys Osypenko, Alex Fratzl, Olexiy Kochubey, Bernhard Bettler, Ralf Schneggenburger
Journal: Neuron (2018)
Abstract LB-248: Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in cancer
Authors: Iqbal Mahmud, Timothy J. Garrett, Ryan Stowe, William R. Roush, Daiqing Liao
Journal: Cancer Research (2018)

Abstract An increased rate of lipid production is a hallmark metabolic feature in cancer cells, which provides energy supplies, building blocks for membrane biogenesis, and signaling molecules for increased cancer cell proliferation. Current chemotherapeutic strategies targeting lipid metabolism have shown significant limitations, and as such, there is great interest in discovering novel therapies that effectively inhibit lipid production in cancer cells. Class I histone deacetylases (HDACs 1-3) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as novel anticancer drugs. Interestingly, HDAC inhibitors (HDACi) have been shown to decrease lipid production in different cells by modulating key genes in cholesterol synthesis, uptake, and efflux. However, effects of HDACi in lipid biosynthesis of cancer remains poorly studied. We have discovered a novel class of HDACi with a previously undescribed benzoylhydrazide scaffold. These new inhibitors are highly selective and potent to the class I HDACs (HDAC1, HDAC2, and HDAC3). Using global lipidomics approach by Ultra High-Performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS), we found that a novel optimized analog, SR-4370, exhibits potent inhibition of lipid production in cells of diverse cancer types. Strikingly, SR-4370 in combination with entinostat, a benzamide analog of class I HDAC inhibitor currently in multiple clinical trials for treating breast cancer and other types of solid tumors, exhibits synergistic effects on inhibition of lipid production in cancer cells. We will present lipidomic profiling data from cells and xenograft tumors after treatment with SR-4370/entinostat, and discuss mechanisms of action for these distinct HDACi in inhibiting lipid production. In summary, our findings provide a rationale for inhibiting lipogenesis using isoform-selective HDACi in cancer therapy. Citation Format: Iqbal Mahmud, Timothy J. Garrett, Ryan Stowe, William R. Roush, Daiqing Liao. Chemically distinct class I HDAC inhibitors synergize to inhibit global lipid metabolism in 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 LB-248.
Synchronous bilateral breast cancer (SBBC): Concordance of receptor status between right and left breast.
Authors: Palak Desai, Eduardo Braun, Irene Dehghan-Paz, Paolo Gattuso, Jeff Canar, Melody A. Cobleigh
Journal: Journal of Clinical Oncology (2012)

572 Background: This analysis was prompted by a patient who presented with SBBC who had and ER+, HER2- cancer in one breast and an ER-, HER2+ cancer in the other. Since both breasts have the same genetic background and environmental exposures, concordance should be virtually identical unless other factors are at play. Methods: SBBC was defined as bilateral cancer diagnosed concurrently or within 6 months of each other. Cases were identified retrospectively from patients seen at Rush University Medical Center. This analysis was limited to invasive SBCC (ISBBC). Estrogen receptor (ER) and Her2/neu (HER2) status were assessed according current ASCO/CAP guidelines. Correlation between ER and HER2 status was determined using κ statistic. Results: From January 1998 to December 2012, 33 cases of ISBBC were diagnosed. In 65% of cases synchronous disease was diagnosed concurrently. The average age at diagnosis was 56. The majority were multiparous and 79% post menopausal. About half of the patients (55%) had at least one first degree relative with a history of breast or ovarian cancer and 9% of the cohort had a deleterious mutation in BRCA1 or BRCA2. Infiltrating ductal was most common (74%) followed by infiltrating lobular (21%). 53% of breasts specimens also contained ductal carcinoma in situ. 68% of tumors were ER positive and 8% were HER2 positive. Concordance in ER status was seen in 73% of cases (kappa coefficient 0.14) and in HER2 status was 64% (Kappa coefficient 0.35). Conclusions: Despite identical hereditary and environmental exposure, some patients develop ISBBC cancers with discordant receptor status. While this is the exception, it suggests that other factors influence important tumor characteristics. [Table: see text]
MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning
Authors: Chun-MeiCao, YanZhang, NoahWeisleder, ChristopherFerrante, XianhuaWang, FengxiangLv, YiZhang, RuishengSong, MoonsunHwang, LiJin, JiaojiaoGuo, WeiPeng, GengLi, MiyukiNishi, HiroshiTakeshima, JianjieMa, Rui-PingXiao
Journal: Circulation (2010)

Background— Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3β [GSK3β] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood. Methods and Results— In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/reperfusion-induced decrease in MG53 expression. MG53 deficiency incre...
Abstract 4781: Changes in intracellular signaling following chronic FGFR inhibition in urothelial bladder cancer models
Authors: Isabel S. Jerchel, Atanas Kamburov, Ralf Lesche, Sabine Zitzmann-Kolbe, Alexander Walter, Peter Ellinghaus, Dominik Mumberg, Oliver Politz, Sylvia Gruenewald
Journal: Cancer Research (2018)

Abstract Preclinical and clinical studies have validated the therapeutic potential of FGFR inhibition in urothelial bladder cancer (UBC) patients with FGFR genetic aberrations. Rogaratinib is a potent small-molecule pan-FGFR inhibitor being studied in phase I trials in UBC. Here, we studied the effects of chronic exposure of bladder cancer cells in vitro to FGFR inhibition by rogaratinib to identify changes in signaling and gene expression patterns that may identify possible drug combinations that may enhance efficacy of rogaratinib and help overcome inherent and/or acquired treatment resistance. Cell proliferation in response to rogaratinib was evaluated using crystal violet staining in a panel of 13 UBC cell lines. Continuous culture of two cell lines–JMSU1 and RT112–with either constant or increasing concentrations of rogaratinib in several independent approaches generated the resistant sublines, JMSU1-R1 to -R4 and RT112-R1 to -R4. In both cellular models rogaratinib resistance (defined as &amp;gt;30-fold [JMSU1] or &amp;gt;100-fold [RT112] difference in absolute IC50 of sublines vs. parental lines) arose reproducibly and with various treatment schedules. Morphologic changes were also observed. Transcriptomic (RNAseq) and proteomic (R&amp;D Systems proteome profiler arrays) analyses of these cell lines or rogaratinib-treated versus untreated parental cells, respectively, revealed changes that co-occur with the development of resistance. Analysis of the phospho-proteome showed increased phosphorylation of several receptor tyrosine kinases compared to the parental cell lines. Phosphorylation levels varied among the 4 resistant sublines that were derived from the same parental line. This resulted in alteration of downstream signaling pathways in rogaratinib-treated sublines compared to parental cell lines. In conclusion, exposure of selected bladder cancer cell lines to rogaratinib resulted in development of resistance and changes in FGFR signaling and gene expression pathways that may identify strategies to optimize treatment with FGFR inhibitors. Citation Format: Isabel S. Jerchel, Atanas Kamburov, Ralf Lesche, Sabine Zitzmann-Kolbe, Alexander Walter, Peter Ellinghaus, Dominik Mumberg, Oliver Politz, Sylvia Gruenewald. Changes in intracellular signaling following chronic FGFR inhibition in urothelial bladder cancer models [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 4781.
Abstract 2488: Functional characterization of nuclear TYRO3 in colorectal cancer
Authors: Shaw-Jenq Tsai, Chun-Wei Chien, Sih-Yu Chen, Shao-Chieh Lin, Bo-Wen Lin, Jenq-Chang Lee
Journal: Cancer Research (2018)

Abstract Colorectal cancer is one of most common death-related cancers worldwide. Aberrant expression of oncogenes is regarded as a predominant factor in colorectal cancer development. TYRO3 belongs to TAM (TYRO3, AXL, and MER) family, which is a subfamily of receptor tyrosine kinases. Our previous study discovered TYRO3, an oncogene overexpressed in colorectal cancer, promotes cell proliferation, metastasis, and tumor progression. Herein, we further identified that TYRO3 is present in nucleus of colon cancer cells using immunofluorescence staining in conjunction with confocal microscopy. By staining with three different antibodies recognizing N-terminal, central region, and C-terminal of TYRO3, respectively, we identified that central and C-terminal of TYRO3 is the fragment to be translocated to the nucleus. Transfection of exogenous Myc-TYRO3-GFP fusion protein further confirmed this finding. By bioinformatic tool prediction, we found there is a nuclear localization signal (NLS) and a nuclear export signal (NES) in TYRO3. To evaluate the function of nuclear TYRO3, we mutated NLS of TYRO3 and performed several functional studies. Results of immunofluorescent staining showed that after NLS mutation, TYRO3 cannot be translocated to nucleus, which was accompanied by distorted morphology. Furthermore, cancer cells transfected with NLS-mutated TYRO3 increased activated caspase-3 and number of apoptotic cells, suggesting nuclear localization of TYRO3 is essential for cell survival. Clinical data further support that levels of nuclear TYRO3 are a poor prognostic marker that is positively associated with colon cancer treatment failure and malignancy. These data support that nuclear TYRO3 is important for colon cancer cell survival and is a valuable biomarker for prognosis. Citation Format: Shaw-Jenq Tsai, Chun-Wei Chien, Sih-Yu Chen, Shao-Chieh Lin, Bo-Wen Lin, Jenq-Chang Lee. Functional characterization of nuclear TYRO3 in colorectal 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 2488.
Death certification reforms are an opportunity for wider quality improvement
Authors: Walid Al-Wali, Anand Deshmukh, Manal Hamed, Adila Shaukat
Journal: BMJ (2018)

Luce and Smith discuss death certification reforms,12 which will also improve other aspects of healthcare quality.

Mortality is the most important performance indicator for healthcare organisations. Local programmes of mortality review—including establishing whether the death was avoidable and what lessons can be learned to reduce …
Prognostic Value of Cardiac Magnetic Resonance Stress Tests
Authors: CosimaJahnke, EikeNagel, RolfGebker, ThomasKokocinski, SebastianKelle, RobertManka, EckartFleck, IngoPaetsch
Journal: Circulation (2007)

Background— Adenosine stress magnetic resonance perfusion (MRP) and dobutamine stress magnetic resonance (DSMR) wall motion analyses are highly accurate for the detection of myocardial ischemia. However, knowledge about the prognostic value of stress MR examinations is limited. We sought to determine the value of MRP and DSMR, as assessed during a single-session examination, in predicting the outcome of patients with known or suspected coronary artery disease. Methods and Results— In 513 patients (with known or suspected coronary disease, prior coronary artery bypass graft, or percutaneous coronary intervention), a combined single-session magnetic resonance stress examination (MRP and DSMR) was performed at 1.5 T. For first-pass perfusion imaging, the standard adenosine stress imaging protocol (140 μg · kg−1 · min−1 for 6 minutes, 3-slice turbo field echo–echo-planar imaging or steady-state free precession sequence, 0.05 mmol/kg Gd-DTPA) was applied, and for DSMR, the standard high-dose dobutamine/atropin...
Design Principles and Multifunctionality in Cell Encapsulation Systems for Tissue Regeneration
Authors: Clara R. Correia, Rui L. Reis, João F. Mano
Journal: Advanced Healthcare Materials (2018)

Abstract Cell encapsulation systems are being increasingly applied as multifunctional strategies to regenerate tissues. Lessons afforded with encapsulation systems aiming to treat endocrine diseases seem to be highly valuable for the tissue engineering and regenerative medicine (TERM) systems of today, in which tissue regeneration and biomaterial integration are key components. Innumerous multifunctional systems for cell compartmentalization are being proposed to meet the specific needs required in the TERM field. Herein is reviewed the variable geometries proposed to produce cell encapsulation strategies toward tissue regeneration, including spherical and fiber‐shaped systems, and other complex shapes and arrangements that better mimic the highly hierarchical organization of native tissues. The application of such principles in the TERM field brings new possibilities for the development of highly complex systems, which holds tremendous promise for tissue regeneration. The complex systems aim to recreate adequate environmental signals found in native tissue (in particular during the regenerative process) to control the cellular outcome, and conferring multifunctional properties, namely the incorporation of bioactive molecules and the ability to create smart and adaptative systems in response to different stimuli. The new multifunctional properties of such systems that are being employed to fulfill the requirements of the TERM field are also discussed.
Abstract 355: Post-translational Modification of Histone Variants in Cardiac Hypertrophy
Authors: MickeyMiller, AmanMakaju, LiWang, SarahFranklin
Journal: Circulation Research (2014)

While global changes in gene expression are a hallmark of cardiac hypertrophy, much less is known regarding the epigenetic factors driving these changes. Local chromatin packing and gene accessibility, which governs transcriptional status, has been correlated with specific post-translational modifications on the histone tails of nucleosomes occupying these regions. However, the specific alterations in histone post-translational modifications driving gene expression changes during cardiac hypertrophy are largely unknown. To identify myocyte specific changes in histone post-translational modifications during cardiac hypertrophy we performed label-free quantitation of nuclear proteins from isolated neonatal rat ventricular myocytes exposed to the hypertrophic agonists, phenylephrine and isoproterenol. Peptide samples were analyzed on a Thermo Orbitrap Velos Pro mass spectrometer using CID & HCD fragmentation. Differential expression analysis was performed using the Progenesis LC-MS software where modified hi...