tbuckley/cabot-search huggingface dataset:
Distinct Architecture of Lymphatic Vessels Induced by Chimeric Vascular Endothelial Growth Factor-C/Vascular Endothelial Growth Factor Heparin-Binding Domain Fusion Proteins
Authors: TuomasTammela, YulongHe, JohannesLyytikkä, MichaelJeltsch, JohannaMarkkanen, KatriPajusola, SeppoYlä-Herttuala, KariAlitalo
Journal: Circulation Research (2007)

Vascular endothelial growth factor (VEGF)-C and VEGF-D are composed of the receptor-binding VEGF homology domain and a carboxy-terminal silk homology domain that requires proteolytic cleavage for growth factor activation. Here, we explored whether the C-terminal heparin-binding domain of the VEGF165 or VEGF189 isoform also containing neuropilin-binding sequences could substitute for the silk homology domain of VEGF-C. Such VEGF-C/VEGF–heparin-binding domain chimeras were produced and shown to activate VEGF-C receptors, and, when expressed in tissues via adenovirus or adeno-associated virus vectors, stimulated lymphangiogenesis in vivo. However, both chimeras induced a distinctly different pattern of lymphatic vessels when compared with VEGF-C. Whereas VEGF-C–induced vessels were initially a dense network of small diameter vessels, the lymphatic vessels induced by the chimeric growth factors tended to form directly along tissue borders, along basement membranes that are rich in heparan sulfate. For example...
Abstract 164: Ston2 knockdown promotes stem-like properties via dnmt1-mediated muc1 upregulation in ovarian cancer
Authors: Shanshan Xu
Journal: Cancer Research (2018)

Abstract Cancer stem cells possess the ability of self-renewal, unlimited proliferation,and non-sensitivity to physical and chemical factors, which is regarded to be a cause of ovarian cancer recurrence, but the mechanism is currently unclear. We found that the expression of STON2 was significantly lower in ovarian cancer-stem like cells by LC-MS/MS-based label free quantitative proteomics approach and western blot validation. STON2 knockdown upregulated the expression of the CSC-related markers in protein level, increased the spheroids number and CD44+CD24−proportion. Besides, in vivo xenograft experiments, the volume of tumors from the shSton2 group were much bigger compared with the shNC group. Moreover, STON2 overexpression decreased the CSC-related markers and inhibited the spheroids number compared with the control group. Transcriptome sequencing data showed that MUC1 is negative correlation with STON2, which were verificated by RT-PCR and western blot analysis. Subsequently, we found that MUC1 mediated the role of STON2 in regulation of stem-like properties in ovarian cancer. MUC1 knockdown resulted in a significant decrease in the sphere-forming ability, CSC-related markers and CD44+CD24−proportion. In addition, MUC1 overexpression caused an increment of CSC-related markers expression and CD44+CD24−proportion. Furthermore, we found that the reducing of sphere-forming ability caused by STON2 overexpression was rescued by MUC1 overexpression. As MUC1 can be regulated through epigenetic mechanisms, we found that DNA methylation inhibitor Azacitidine was able to rescue the upregulation of MUC1 by STON2. The DNA methylation levels of MUC1 in one CpG-rich region were then evaluated with pyrosequencing, and the data displayed that the siSton2 group is lower than the control group. Furthermore, we found that the DNMT1 as a member of the DNA methyltransferase family decreased following with STON2 knockdown in protein level, rather than in mRNA level. We thus knock down DNMT1 using specific siRNA, and found that MUC1 overexpression both in mRNA level and protein level. In this study, we focused primarily on STON2 repression leading to DNMT1 downregulation and MUC1 activation is a main mechanism underlying the maintenance of stem-like properties in ovarian cancer. Citation Format: Shanshan Xu. Ston2 knockdown promotes stem-like properties via dnmt1-mediated muc1 upregulation in ovarian 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 164.
Abstract 186: Small-molecule inhibition of cathepsins L and K as potential therapeutics for macrophage-driven breast cancer
Authors: Samantha S. Dykes, Dietmar W. Siemann
Journal: Cancer Research (2018)

Abstract Tumor-associated macrophages secrete many factors including proteases and growth factors, which ultimately promote the metastatic phenotype of mammary tumors. Due to their numerous pro-tumor functions, tumor-associated macrophages represent an attractive cell population for stromal-targeted anti-cancer therapies. Interleukin-4 stimulation promotes macrophage differentiation from a baseline M0 state to a more pro-tumorigenic M2 phenotype, which is often associated with increased expression of proteases including the lysosomal cathepsin L. Cathepsin L is important in both macrophage and tumor cell invasion, whereby secreted cathepsin L degrades the extracellular matrix allowing for cell infiltration. M0 to M2 differentiation was not accompanied by an overall increase in the protein expression of cathepsin L, however, secreted cathepsin L was increased in the M2 macrophage population. The present study examined the role of cathepsin L in M0 to M2 differentiation and macrophage-mediated tumor cell invasion using the novel cathepsin L/K inhibitors KGP94 and KGP207 [Dr. Kevin Pinney, Baylor University]. Boyden chamber assays revealed that KGP94 and KGP207 prevented in vitro M2 macrophage invasion and reduced macrophage-stimulated invasion of 4T1 murine breast cancer cells. KGP94 and KGP207 treatment also partially prevented IL-4-stimulated M0 to M2 differentiation of macrophages as determined by a decrease in the IL-4-induced expression of the M2 marker Arginase-1 upon drug treatment. Furthermore, exogenous recombinant cathepsin L partially stimulated the expression of Arginase-1 in M0 macrophages. Together, these data suggest that cathepsin L may play a role in macrophage M0 to M2 differentiation. In summary, the novel cathepsin L/K inhibitors KGP94 and KGP207 altered M0 to M2 differentiation, reduced macrophage invasion, and reduced macrophage-stimulated invasion of breast cancer cells. These data highlight the importance of cathepsin L in macrophage functions and suggest that cathepsin inhibition strategies may be therapeutically beneficial by impairing the progression of tumors, particularly those with high recruitment of M2 macrophages. Citation Format: Samantha S. Dykes, Dietmar W. Siemann. Small-molecule inhibition of cathepsins L and K as potential therapeutics for macrophage-driven breast 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 186.
Abstract 2948: Synergistic effect of combining Akt inhibitor SC66 with anticancer drugs cisplatin and paclitaxel in chemoresistant ovarian cancer cells
Authors: Yi-Hui Wu, Cheng-Yang Chou
Journal: Cancer Research (2018)

Abstract Background and aims Akt plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether Akt inhibition by SC66 is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with chemotherapy drugs. Methods Using eight human ovarian cancer cell lines, we determined the effect of SC66 by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, western blot, and apoptosis assays. We evaluated the association between phospho-Akt/mTOR, COL11A1 and SC66 sensitivity. We also determined the effect of SC66 on tumor growth using mice inoculated with human ovarian cancer cells. Results Cell sensitivity to SC66 was inversely correlated with the expressions of phosphorylation of Akt and COL11A1, and cisplatin resistance. SC66 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase. SC66 also attenuated the expression of TWIST1 and Mcl-1, important factors in invasiveness and anti-apoptosis. SC66 sensitizes chemo-resistant cells to cisplatin and paclitaxel treatment, and enhanced apoptosis in the chemo-resistant cells. In addition, SC66 inhibited COL11A1 expression via decreasing the binding activity of c/EBPβ and NF-YA to the COL11A1 promoter, which was associated with chemoresistance and cell invasiveness respectively. In vivo, treatment with SC66 enhanced the therapeutic efficacy of cisplatin and paclitaxel in mouse xenograft. Conclusions These results indicate the SC66 could have therapeutic efficacy in human ovarian cancers. Citation Format: Yi-Hui Wu, Cheng-Yang Chou. Synergistic effect of combining Akt inhibitor SC66 with anticancer drugs cisplatin and paclitaxel in chemoresistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2948.
Abstract 247: Digitization of Electrocardiogram from Telemetry Prior to In-Hospital Cardiac Arrest
Authors: LuWang, RezaSoroushmehr, KayvanNajarian, MinaAttin
Journal: Circulation (2014)

Background: Telemetry is commonly used to alert clinicians to respond to in-hospital cardiac arrest (I-HCA). Analyzing electrocardiogram (ECG) over an extended period of time prior to I-HCA is often time consuming because digital records of the ECG from telemetry are not available in the majority of hospitals. The objective of this study was to develop an algorithm to digitize full disclosure ECG papers in order to perform automated measurements. Methods: In a multi-center study, full-disclosure ECG papers (25 mm/s paper speed) within one hour of I-HCA of 42 cardiovascular patients with initial rhythms of pulseless electrical activity (PEA) and asystole were obtained from telemetry. Digital ECGs from one of the centers was also available for seven of these patients with a sampling rate of 500 Hz. The duration for each full-disclosure ECG paper was either 7.6 or 10.8 seconds as dictated by each hospital’s monitoring system. An algorithm to digitize the full-disclosure ECG papers was developed according to ...
Abstract 3942: The fraction of garlic protein(s) affect HCC via regulation of angiogenesis
Authors: Nabanita Chatterjee, Subhadip Das, Prajnamoy Pal, Krishna Das Saha
Journal: Cancer Research (2018)

Abstract Cancers are leading cause of human mortality. Most of deaths are due cancer because of its high resistance to the chemotherapeutic drugs. Thus, there is an ongoing demand for generation of new potent and more effective therapies for cancer treatment. Hepatocellular carcinoma (HCC), is the most leading cause of cancer-related death in all over the world (seems to more than 80% of death cases in USA). It is frequently linked with continuous hepatocytes death, inflammatory cell infiltration, and compensatory liver regeneration with higher angiogenic rate. Considering the different signaling process during this tumorigenesis with the involvement of new ‘lead' identification of various sources, desire to be less toxic and higher bioavailability. The use of natural or its active metabolic component(s) has begun to emerge as a potential innovative approach in medicinal research to deliver bioactive entities. Thus, garlic has already proven as the therapeutic implication on immune system and cancer due to presence of sulfur compound. But the role of active protein fraction present in fresh garlic is still not revealed yet. In our study, we are isolated an active garlic protein from fresh garlic aqueous extract with molecular weight about 40-45kD. This Garlic protein (GP) having non-cytotoxic to human/murine normal cells, could induce apoptosis in human HepG2 cells, as characterized by phosphatydylserine serine exposure, DNA fragmentation, alteration with loss of mitochondrial membrane potential and cytochrome C release, activation of series of caspases, other physiochemical changes lead to induce cancer cell death. This study also focused that the GP effectively suppressed DEN induced liver inflammation and hyperplasia in murine also decline in lipid peroxidation and changes in enzymic antioxidants and biochemical parameter with improvement of their survival rate. It reduced the elevated level of cytokines and growth factors in hepatocytes from liver fibrosis bearing mice. Thus, finding indicated that, GP may induce apoptosis and in hyper proliferating cancer cells via altering cytokines-chemokines level with tumor growth regulation in carcinogen exposed rodent system. Future direction, we are proposing to execute the experiments on p53-/- and cMyc-/- deficient mice to find out the role of GP in these circumstances. Citation Format: Nabanita Chatterjee, Subhadip Das, Prajnamoy Pal, Krishna Das Saha. The fraction of garlic protein(s) affect HCC via regulation of angiogenesis [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 3942.
Abstract 1912: A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors
Authors: Bret David Wallace, Jeffrey Hymes, Matthew Redinbo, Ward Peterson
Journal: Cancer Research (2018)

Abstract Many drugs are inactivated by liver UGT enzymes and reactivated by enteric bacterial β-glucuronidases (GUS), an axis of drug metabolism that contributes to gut toxicities of anti-neoplastic agents, NSAIDs, and potentially other drug classes. For example, toxic reactivation of irinotecan by E. coli GUS is the causative event leading to intense, delayed diarrhea. Receptor tyrosine kinase (RTK)-targeted cancer drugs that undergo this UGT-GUS axis of metabolism are also associated with a high incidence of diarrhea. However, glucuronides of RTK inhibitors (RTKi) are not substrates of E. coli GUS. We recently reported that the human gut microbiome expresses nearly 300 distinct GUS enzymes (GUSome). The objective of this work is to identify the GUS enzyme(s) capable of metabolizing the glucuronide of the RTKi, sorafenib, that may contribute to sorafenib-induced diarrhea. We used UGT1A9 supersomes to make sorafenib-glucuronide (S-G) from commercially purchased sorafenib. S-G was screened against a library of 15 purified GUSome enzymes to identify the specific GUS orthologs that can cleave S-G, which was determined by monitoring sorafenib absorbance at 280 nm. Similar approaches were used to identify GUS enzymes that can cleave other RTKi's. Of the GUS enzymes evaluated for cleavage of S-G, only the GUS enzyme from an uncultured Eubacterium species was active. The structurally similar regorafenib-glucuronide and two glucuronides of other RTKi's (axitinib and imatinib) are also substrates of Eubacterium GUS. All four RTKi's are associated with diarrhea in at least 40-60% of patients. In contrast to E. coli GUS, very little is known about Eubacterium GUS. We have identified a set of RTKi-glucuronides as the first substrates of Eubacterium GUS, which may contribute to diarrhea associated with targeted anti-cancer drugs. Citation Format: Bret David Wallace, Jeffrey Hymes, Matthew Redinbo, Ward Peterson. A microbial glucuronidase target implicated in intestinal reactivation of tyrosine kinase inhibitors [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 1912.
Abstract O-3: A β1-Adrenergic Receptor/β-Arrestin1-Regulatable MicroRNA, MiR-150 Protects the Mouse Heart from Ischemic Injury by Repressing Pro-apoptotic Egr2 and P2x7r
Authors: Il-manKim, YaopingTang, YongchaoWang, Kyoung-miPark, QiupingHu
Journal: Circulation Research (2014)

MicroRNA (miR)-150 is down-regulated in patients with acute myocardial infarction (AMI), atrial fibrillation, dilated and ischemic cardiomyopathy as well as in various mouse heart failure (HF) models. Circulating miR-150 has been recently proposed as a better biomarker of HF than clinically used markers such as brain natriuretic peptide. We recently showed that β-arrestin1-biased β1-adrenergic receptor (β1AR) cardioprotective signaling activated by the β-arrestin-biased β-blocker, carvedilol (Carv) stimulates the processing of miR-150 in the heart (see figure A). However, the potential role of miR-150 in ischemic injury and HF is unknown. Here, we show that genetic deletion of miR-150 in mice causes abnormalities in cardiac structural and functional remodeling after MI. The cardioprotective roles of miR-150 during ischemic injury were attributed to repression of the pro-apoptotic genes egr2 (zinc binding transcription factor induced by ischemia) and p2x7r (pro-inflammatory ATP receptor) [see figure B]. Th...
Abstract 4277: Modeling selectin-coated microprobe adhesion to selectin ligands heterogeneously expressed on cancer tissues
Authors: Eric Martin, Douglas Goetz, Monica Burdick
Journal: Cancer Research (2018)

Abstract The transition to an era of functional glycomics has created a need for the development of novel techniques to assess complex glycoconjugate cellular adhesion molecules (e.g., selectin ligands) that may be involved in capturing and mediating the adhesion circulating tumor cells to distant sites. Cell line, knockout, and selectin antagonist evidence suggests that selectin/selectin-ligand interactions are involved in metastasis. However, identification and characterization of functional selectin ligand expression on cancer tissue (i.e., CTC origin site) remains challenging due to the inherent heterogeneity of tissues magnified by the "catch-slip" and stochastic nature of selectin/selectin-ligand bonds. We have developed a flow-based assay known as dynamic biochemical tissue analysis (DBTA) that involves the perfusion of selectin-coated microprobes over tissues at physiologic wall shear rates. Using DBTA, the expression of functional selectin ligands has been detected (i.e., specific binding and rolling of selectin-coated microprobes) on tissue from multiple solid tumors at primary and metastatic sites. Although DBTA provides evidence that multiple types of cancer can express complicated glycoconjugate structures (selectin ligands) that are able to bind to selectins in a shear-dependent manner, the challenge of the assay is in the analysis of the large amounts of image sequence data generated. This analysis is further complicated by the dynamic behavior of selectin-coated microprobe adhesion to selectin ligands expressed on a heterogeneous cancer tissue surface. To extract the biophysical underpinnings towards the development of this prospective in vitro diagnostic, a mathematical model was devised to refine the design space of this flow assay. The model is semi-empirical and consists of a coupled set of stochastic, 4D partial differential equations that account for the transport of probes to the tissue surface as well as the dynamics of probe adsorption to a heterogeneous tissue surface. Empirical data were obtained by processing image sequences with machine-learning, template-matching algorithms to conduct image segmentation, followed by probe tracking over time using a program written in Python. The empirical data displayed a stochastic adsorption profile and showed agreement with the model equations that were solved numerically using a finite difference scheme written in C++. Altogether, this approach is able to successfully bridge the gap between the seemingly random rolling interactions observed in the flow assay and the underlying physical mechanisms. Citation Format: Eric Martin, Douglas Goetz, Monica Burdick. Modeling selectin-coated microprobe adhesion to selectin ligands heterogeneously expressed on cancer tissues [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 4277.
Ste20-Related Kinase SLK Phosphorylates Ser188 of RhoA to Induce Vasodilation in Response to Angiotensin II Type 2 Receptor Activation
Authors: ChristopheGuilluy, MalvyneRolli-Derkinderen, LaurentLoufrani, AnneBourgé, DanielHenrion, LucSabourin, GervaiseLoirand, PierrePacaud
Journal: Circulation Research (2008)

The small G protein Rho signaling pathways are recognized as major regulators of cardiovascular functions, and activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Recent evidence suggests that modulation of Rho protein signaling by phosphorylation of Rho proteins provides an additional simple mechanism for coordinating Rho protein functions. Phosphorylation of RhoA by cAMP- or cGMP-activated kinase on Ser188 induces cytosolic sequestration of RhoA through increased interaction with guanine dissociation inhibitor, thereby resulting in inhibition of RhoA-dependent functions. Here we show that stimulation of angiotensin II (Ang II) type 2 receptor (AT2R) in vascular smooth muscle cells induces Ser188 phosphorylation of RhoA independently of cAMP- or cGMP-activated kinase. We identify the Ser/Thr kinase Ste20-related kinase SLK as a new kinase phosphorylating RhoA on Ser188. Activation of the signaling cascade involving Src hom...
Idiopathic Hypertrophic Subaortic Stenosis
Authors: Stuartfrank, Eugenebraunwald
Journal: Circulation (1968)

While considerable information concerning the hemodynamic and angiographic features of idiopathic hypertrophic subaortic stenosis (IHSS) is available, data concerning the natural history of the disease are limited. The clinical courses of 126 patients with hemodynamically documented IHSS, examined repeatedly for up to 12 years, were analyzed. The older patients tended to be more severely symptomatic. Although the course was extremely variable, the patients who were asymptomatic initially tended to remain so, while those who were more disabled generally deteriorated, died, or improved spontaneously. Bacterial endocarditis occurred in three patients. Ten patients died as a consequence of the natural history of IHSS; six of these deaths were unexpected. Sudden deaths occurred usually in patients with no or mild obstruction, and in patients with both the familial and sporadic forms of the disease. Atrial fibrillation was observed in 8% of the patients, and abnormalities of atrioventricular conduction, in 30%....