tbuckley/cabot-search huggingface dataset:
Papillary Muscles Do Not Attach Directly to the Solid Heart Wall
Authors: LeonAxel
Journal: Circulation (2004)

Background— The papillary muscles (PMs) play an important role in normal cardiac function, helping to prevent leakage through the AV valves during systole. The nature of their attachment to the heart wall can affect the understanding of their function. This attachment is conventionally portrayed as a direct connection of their bases to the solid portion of the heart wall. X-ray multidetector CT provides a new, noninvasive way to investigate this connection in vivo. Methods and Results— With the use of x-ray multidetector CT with interactive 3D reconstruction, the bases of the PMs are seen to attach to the trabeculae carneae lining the ventricular wall rather than directly to the solid portion of the wall, as has been conventionally believed. This is true for both the left and right ventricular PMs. Conclusions— This new picture of the geometry of the attachment of the PMs to the heart wall may have important implications for the understanding of their function, including the nature of the transmission of ...
Abstract 5045: Inflammation is upregulated in the normal colonic epithelium and stroma of <i>Apc</i>+/Min-FCCCmice with colon tumors
Authors: Alyssa A. Leystra, Lisa Vanderveer, Yan Zhou, Harry S. Cooper, Sergei Grivennikov, Margie L. Clapper
Journal: Cancer Research (2018)

Abstract The Apc+/Min-FCCC mouse harbors a point mutation in the Apc tumor suppressor gene and is highly susceptible to the development of multiple colon tumors. Despite being maintained for many years as an inbred colony, Apc+/Min-FCCC mice are heterogeneous with respect to the time to colon tumor development and the number of colon tumors that ultimately form. This model therefore serves as a powerful tool with which to better understand the earliest events that lead to tumorigenesis. Identification of early alterations in these animals may provide targets for effective, long-term tumor prevention. The goal of this study was to characterize early changes in gene expression in the nonneoplastic colonic epithelium and stroma that may contribute to tumor formation in Apc +/Min-FCCC mice. Animals were defined as ‘tumor-bearing' if they harbored at least one gross colon tumor at necropsy. No lesions were detected at necropsy in the remaining animals (‘tumor-free'). Normal tissue was collected for analysis from the distal colon at least 1 cm away from the nearest tumor. Histologically-normal epithelial and stromal cells were microdissected from frozen tissue sections. Gene expression profiling was performed using the Agilent Mouse 4x44K microarray chip. Differentially expressed genes were selected using an FDR of 10% and a ≥ 2-fold change in gene expression. Gene set enrichment analyses confirmed the enrichment of stromal genes in samples of isolated stroma (p&amp;lt; 0.05). Numerous genes were differentially expressed in tumor-free vs. tumor-bearing ApcMin/+ mice, in both the epithelial and stromal compartments. Gene Ontology enrichment analyses revealed the associated biological processes that were dysregulated, including inflammation, immune cell migration, and response to bacterium (FDR&amp;lt;0.1%). These findings indicate that inflammatory processes are altered in the nonneoplastic colon well in advance of tumor formation and represent promising targets for preventive intervention. Citation Format: Alyssa A. Leystra, Lisa Vanderveer, Yan Zhou, Harry S. Cooper, Sergei Grivennikov, Margie L. Clapper. Inflammation is upregulated in the normal colonic epithelium and stroma of Apc+/Min-FCCCmice with colon 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 5045.
Abstract 19364: C-Kit+ Cardiac Progenitor Cells are Important in Cardiomyocytes Generation in vivo in Response to Sfrp2
Authors: Jose Gomez, Conrad Hodgkinson, Alan Payne, Jeffrey Scmeckpeper, Lunan Zhang, Lan Mao, Victor Dzau
Journal: Circulation (2015)

Introduction: Resident c-Kit+ cardiac progenitor cells (CPCs) differentiation into cardiomyocytes in vivo is controversial. Using lineage tracing and gene ablation techniques we documented that the Wnt signaling modulator Sfrp2 substantially increased differentiation of c-Kit+ CPCs into cardiomyocytes in post-MI heart and restored cardiac function. Methods: c-Kit-CreERT2/mTeG mice were used where the c-Kit promoter drives expression of a tamoxifen (TX)-inducible Cre. Upon TX treatment Cre-mediated recombination drives expression of eGFP exclusively in c-Kit cells. Mice were crossed with a Diphtheria toxin receptor (DT) strain to selectively ablate heart c-Kit cells. Mice were subjected to myocardial infarction. 2 days later, mice were injected with Sfrp2 (0.5 μg) or saline at the infarct border zone. Heart tissue was analyzed 2 months post-MI for eGFP expression and various markers by microscopy. Results: c-Kit-CreERT2/mTeG model was tested. eGFP expression had no effect on in vitro c-Kit CPC differentiat...
Augmented Expression of Neuronal Nitric Oxide Synthase in the Atria Parasympathetically Decreases Heart Rate During Acute Myocardial Infarction in Rats
Authors: YoshihitoTakimoto, TakeshiAoyama, KoichiTanaka, ReikoKeyamura, YoshikiYui, ShigetakeSasayama
Journal: Circulation (2002)

Background— Nitric oxide (NO) synthesized within sinoatrial cells recently has been shown to participate in the autonomic control of heart rate. We hypothesized that NO in the neuronal cells in the heart was increased and parasympathetically regulated heart rate after myocardial infarction (MI). Methods and Results— We examined heart rate dynamics and neuronal NO synthase (nNOS) expression and activities in the atria of rats with MI 1, 3, 7, and 14 days after MI (n=7 to 22 for each group). Both the mRNA levels of nNOS in the atria determined by competitive reverse transcriptase-polymerase chain reaction and the protein levels determined by Western blotting were significantly increased compared with controls 1, 3, and 7 days after MI. nNOS activity in the atria 1 day after infarction was also increased in MI rats. nNOS immunoreactivity was observed in nerve fibers in the atria. After infusion of a specific inhibitor of nNOS and iNOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM) (50 mg/kg IV), heart rate wa...
간세포암종 환자에서 병기, 간기능 및 치료법에 따른 3년 생존율 분석
Authors: 박경우
Journal: Clinical and Molecular Hepatology (2006)

목적: 간세포암종은 국내 암 발생 등록분율 3위를 차지하고 예후 또한 매우 불량한 암종으로, 여러 치료법에 따른 성적과 예후 인자를 알아보는 것은 향후 국내 간세포암종 환자들에게 적합한 치료 가이드라인 및 예후 예측 시스템을 개발하는 데 있어 매우 중요한 일이다. 이에 연구자들은 국내 단일 기관에서 진단 및 치...
Abstract 10031: Small Aortic Root Size Has Prognostic Implications Both for Women and Men With Asymptomatic Aortic Stenosis
Authors: Edda Bahlmann, Dana Cramariuc, Jan Minners, Mai Tone Lønnebakken, Simon Ray, Christa Gohlke-Baerwolf, Christoph A Nienaber, Nicolaus Jander, John B Chambers, Karl Heinz Kuck, Eva Gerdts
Journal: Circulation (2015)

Background: Sex-specific analysis of small aortic root has not been reported in asymptomatic aortic stenosis (AS) patients. Methods: We used echocardiographic and outcome data from 1560 patients with asymptomatic initially mild-moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. A small aortic root was defined as an inner diameter at the aortic sinotubular junction &lt; 1.5cm/m in women and &lt; 1.6cm/m in men. Results: A small aortic root was found in 17.4% patients at baseline and independently associated with higher pulse pressure/stroke volume index and aortic root wall thickness, higher pressure recovery, lower LV mass index and female sex in multivariate logistic regression analysis (all p&lt;0.05). In sex-specific multivariate Cox regression analysis, adjusting for the known prognosticators age, hypertension and AS severity and for randomized study treatment, having a small aortic root predicted a 66% higher rate of ischemic cardiovascular events and a 2-fold higher rate of non-haemorrhagic stroke and cardiovascular death (all p&lt;0.05) in men and a 2-fold higher rate of CABG in women (Table). Presence of small aortic root did not influence total mortality or aortic valve replacement in either gender. Conclusion: In asymptomatic AS patients without known cardiovascular disease or diabetes, having a small aortic root was associated with increased rate of cardiovascular events in both women and men. Table. Small aortic root as predictor of different cardiovascular events in multivariate analyses in women and men [HR (95%CI)].
Abstract 3107: Modeling DICER1 syndrome in cells
Authors: Mona K. Wu
Journal: Cancer Research (2018)

Abstract DICER1 is an endoribonuclease central to generating microRNAs (miRNAs), small RNA molecules that downregulate the expression of approximately 30% of protein-coding genes. Germ-line mutations in DICER1 have been identified in patients afflicted with a pleiotropic tumor predisposition syndrome, usually referred to as DICER1 syndrome (OMIM 606241). DICER1 syndrome is thought to originate from a mesenchymal cell bearing a frameshift or nonsense mutation on one allele and a missense mutation affecting the RNase IIIb domain on the other allele. While interest in the role of DICER1 in normal development and pathogenesis has been explored in both the knockout and overexpression context, neither situation is relevant for understanding DICER1 syndrome. We hypothesize that defective DICER1 protein production in a mesenchymal stem cell at a critical time in development leads to altered miRNA populations that, in turn, initiate or prime cells for tumorigenesis. The goal of this study was to develop and characterize a model of the putative tumor-initiating cell namely a mesenchymal stromal cell (MSC) bearing a DICER1 RNase IIIb mutation. SV-40 immortalized mouse mesenchymal stromal cells (MSCs) containing a homozygous floxed exon for DICER1 were ex vivo cre inactivated to produce Dicer-/- MSCs. Into these Dicer-/- MSCs, a FLAG-tagged human DICER1, a FLAG-tagged RNase IIIa mutant DICER1, and a FLAG-tagged RNase IIIb mutant DICER1 were stably introduced. Cells were characterized by Western blot in response to serum starvation and stimulation. Their ability to form anchorage-independent colonies was assessed by soft agar assay pre- and post-oncogene introduction. Transcriptomes were interrogated by gene expression microarray. Results: Alterations in protein expression were observed in cells in response to starvation and stimulation. Certain cell lines were able to produce anchorage-independent colonies. Conclusions: We have created MSCs bearing RNase IIIb-mutated DICER1 to model DICER1 syndrome. We suggest that the ability for an MSC to produce only 3p miRNAs in the presence of an oncogene can allow for anchorage-independent growth. Citation Format: Mona K. Wu. Modeling DICER1 syndrome in 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 3107.
Abstract CT139: Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study
Authors: Antoni Ribas, Theresa Medina, Shivaani Kummar, Asim Amin, Joseph J. Drabick, Minal Barve, Gregory Daniels, Deborah L. Wong, Emmett V. Schmidt, Abraham C. Leung, Robert Janssen
Journal: Cancer Research (2018)

Abstract Background: This phase 1b trial evaluates the safety and antitumor efficacy of the combination of SD-101, a synthetic CpG-oligonucleotide that stimulates Toll-like receptor 9 (TLR9), and pembrolizumab in patients with recurrent Stage IIIC/IV malignant melanoma. Methods: Dose escalation of SD-101 used a modified 3+3 design. SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses over 6 months) at 1, 2, 4, or 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks up to 2 years. Tumor responses were assessed per investigator using RECIST v1.1 taking into account both injected and non-injected lesions. Results: Of the 22 patients, 9 were naïve to anti-PD-1/L1 therapy at baseline and 13 had progressive disease while receiving prior anti-PD-1/L1 therapy. Treatment was well tolerated with no Grade 3 or higher treatment-related AEs in longer term follow up. Among the 9 patients who were anti-PD-1/L1 naïve, best objective responses were CR: 2, PR: 5, PD: 1, not evaluated [NE]: 1. Median PFS, duration of response, and OS have not been reached. Estimated 12 month PFS was 88% and OS was 89%. After a median of 18 months of follow-up, 86% of responses were ongoing. One patient with a PR developed progressive disease after 20 months of treatment. Among patients who had received prior anti-PD-1/L1 therapy, best objective responses were PR: 2, SD: 5, PD: 5, NE: 1. One patient with stable disease and 1 patient with a PR continued on combination therapy without progression for at least 10.5 months. The other 10 patients developed progressive disease ranging from 1.5 to 8 months after enrollment. Percent change in tumor size from baseline in injected and non-injected lesions will also be presented. Conclusion: These early results suggest that combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially provide more clinical responses that are meaningfully durable than PD-1 blockade alone based on historical data. Citation Format: Antoni Ribas, Theresa Medina, Shivaani Kummar, Asim Amin, Joseph J. Drabick, Minal Barve, Gregory Daniels, Deborah L. Wong, Emmett V. Schmidt, Abraham C. Leung, Robert Janssen. Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study [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 CT139.
Abstract 1873: Preclinical activity of tipifarnib in cutaneous T-cell lymphoma
Authors: Rebecca Kohnken, Betina McNeil, Jing Wen, Kathleen McConnell, Francis Burrows, Pierluigi Porcu, Anjali Mishra
Journal: Cancer Research (2018)

Abstract Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma characterized by malignant infiltration of skin-homing CD4+ T-cells, manifesting clinically as patches and plaques on the skin (Wong HK, et al. Br J Haematol 2011). The disease will often progress from an indolent skin-limited form, Mycosis Fungoides (MF), to an aggressive leukemic variant, Sezary Syndrome (SS) (Kohnken R, et al. Curr Hematol Malig Rep 2016). As there are few effective therapies available for advanced-stage CTCL, we sought to explore potential novel therapeutic modalities. Farnesyl transferase inhibitors (FTIs) are a relatively new class of anticancer drugs, the exact mechanism of which is unknown. Tipifarnib is one such FTI, which has demonstrated clinical activity as a single agent in patients with relapsed and refractory lymphomas (Witzig, TE, et al. Blood 2011). We utilized CTCL patient-derived cell lines to evaluate the potential efficacy of tipifarnib in vitro. EC50 doses ranged from 7.5nM for HuT78 to 50nM for SeAx. Importantly, there was no cytotoxic effect on normal donor CD4+ T-cells in vitro. Based on these promising findings, we evaluated tipifarnib in vivo using a recently described interleukin-15 (IL-15) transgenic mouse model of CTCL (Mishra A, et al. Can Discov 2016). Following two weeks of dosing in 5-week old mice, we found a significant decrease in gross lesion severity in tipifarnib-treated mice (0.5±1.22 out of a possible score of 5) compared to vehicle-treated mice (3.33±0.57, p=0.0076). Histologically, IL-15 transgenic mice develop characteristic malignant CD4+ T-cell infiltrates in the dermis and epidermis. Tipifarnib-treated mice, however, have minimal lesions in the skin. These dramatic changes are reflected in a significantly decreased histologic severity score in tipifarnib-treated mice (3.8±0.75 out of a possible score of 7 compared to vehicle-treated mice (7±0, p=0.0002). These findings demonstrate that tipifarnib is active in patient-derived cell lines and the mouse model of cutaneous T-cell lymphoma. Further studies to elucidate the mechanism of antitumor activity of farnesyl transferase inhibition in this cell type are in progress. Citation Format: Rebecca Kohnken, Betina McNeil, Jing Wen, Kathleen McConnell, Francis Burrows, Pierluigi Porcu, Anjali Mishra. Preclinical activity of tipifarnib in cutaneous T-cell 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 1873.
NOTCH3 Expression Is Induced in Mural Cells Through an Autoregulatory Loop That Requires Endothelial-Expressed JAGGED1
Authors: HuaLiu, SimoneKennard, BrendaLilly
Journal: Circulation Research (2009)

Endothelial cells and mural cells (smooth muscle cells, pericytes, or fibroblasts) are known to communicate with one another. Their interactions not only serve to support fully functional blood vessels but also can regulate vessel assembly and differentiation or maturation. In an effort to better understand the molecular components of this heterotypic interaction, we used a 3D model of angiogenesis and screened for genes, which were modulated by coculturing of these 2 different cell types. In doing so, we discovered that NOTCH3 is one gene whose expression is robustly induced in mural cells by coculturing with endothelial cells. Knockdown by small interfering RNA revealed that NOTCH3 is necessary for endothelial-dependent mural cell differentiation, whereas overexpression of NOTCH3 is sufficient to promote smooth muscle gene expression. Moreover, NOTCH3 contributes to the proangiogenic abilities of mural cells cocultured with endothelial cells. Interestingly, we found that the expression of NOTCH3 is depe...
Abstract 5512: Dual inhibition of AXL and FN14 reverses cisplatin resistance in non-small cell lung carcinoma by inducing higher caspase 3 cleavage
Authors: Soumavo Mukherjee, Dhananjay Suresh, Ajit P. Zambre, Anandhi Upendran, Raghuraman Kannan
Journal: Cancer Research (2018)

Abstract Background and Objectives: NSCLC patients undergoing Cisplatin therapy often develop resistance within 9-12 months that decreases treatment efficacy and is the major reason for the low median survival of 10-14 months among stage IV patients. Therefore, resistance is the main therapeutic limitation in the later part of the progressive disease. It has been suggested that suppressed Caspase-3 is one of the major reasons for failure to induce apoptosis by the cell during cisplatin resistance. We hypothesized this resistance to be related to EMT and other survival pathways. Recently, AXL and TWEAK/FN14 pathways have been shown to be upregulated in cisplatin resistant cells causing activation of EMT and survival pathways. Therefore, we examined whether dual inhibition of AXL and TWEAK/FN14 successfully reverses the cisplatin resistance in NSCLC. Materials and Methods: Drug resistant EGFR mutant H1975 and KRAS mutant A549 cells were tested for cisplatin desensitization following knock down of AXL and FN14 inhibition. We studied resensitization by determining the IC50 values in the drug resistant cell lines by treatment with both AXL and FN14 siRNA. We investigated detailed cellular mechanisms imparting resistance by detecting relative levels of Caspase 3, cleaved Caspase 3, PARP, cleaved PARP, p-SRC, p-EGFR, AXL and FN14 by western blotting. Cytochrome-C induced apoptosis was detected by monitoring cytochrome-c released from mitochondria using fluorescence microscopy. Results: Suppression of AXL and FN14 by siRNA treatment resensitized NSCLC to cisplatin and induced apoptosis. IC50 values were decreased significantly following dual inhibition (by more than 200%). A marked increase in cleaved caspase 3 levels was also observed in both mutant cell lines. A subsequent increase in PARP and cleaved PARP levels verified the fact that caspase 3 is indeed responsible for the apoptosis in these cells. Upregulation of p-SRC and eventually p-EGFR failed to suppress the apoptosis through PI3K/AKT pathway. Cytochrome c release from mitochondria further confirmed cellular apoptosis. Conclusion: Our results show that dual inhibition of AXL and TWEAK/FN14 can reverse cisplatin resistance by inducing higher caspase 3 cleavage that can enhance survival of NSCLC patients undergoing chemotherapy. Citation Format: Soumavo Mukherjee, Dhananjay Suresh, Ajit P. Zambre, Anandhi Upendran, Raghuraman Kannan. Dual inhibition of AXL and FN14 reverses cisplatin resistance in non-small cell lung carcinoma by inducing higher caspase 3 cleavage [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 5512.
Labeling of Collagen Type I Templates with a Naturally Derived Contrast Agent for Noninvasive MR Imaging in Soft Tissue Engineering
Authors: Heinz P. Janke, Nihan Güvener, Weiqiang Dou, Dorien M. Tiemessen, Anglita YantiSetiasti, Jozef G. O. Cremers, Paul J. A. Borm, Wout F. J. Feitz, Arend Heerschap, Fabian Kiessling, Egbert Oosterwijk
Journal: Advanced Healthcare Materials (2018)

Abstract In vivo monitoring of tissue‐engineered constructs is important to assess their integrity, remodeling, and degradation. However, this is challenging when the contrast with neighboring tissues is low, necessitating labeling with contrast agents (CAs), but current CAs have limitations (i.e., toxicity, negative contrast, label instability, and/or inappropriate size). Therefore, a naturally derived hemin‐L‐lysine (HL) complex is used as a potential CA to label collagen‐based templates for magnetic resonance imaging (MRI). Labeling does not change the basic characteristics of the collagen templates. When hybrid templates composed of collagen type I reinforced with degradable polymers are subcutaneously implanted in mice, longitudinal visualization by MRI is possible with good contrast and in correlation with template remodeling. In contrast, unlabeled collagen templates are hardly detectable and the fate of these templates cannot be monitored by MRI. Interestingly, tissue remodeling and vascularization are enhanced within HL‐labeled templates. Thus, HL labeling is presented as a promising universal imaging marker to label tissue‐engineered implants for MRI, which additionally seems to accelerate tissue regeneration.