tbuckley/cabot-search huggingface dataset:
Abstract 4791: OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance models
Authors: Marion Libouban, Eleonora Jovcehva, Desiree De Lange, Boudewijn Janssens, Tinne Verhulst, Souichi Ogata, Berthold Wroblowski, Laurence Mevellec, Tianbao Lu, Glen Clack, Timothy Perera
Journal: Cancer Research (2018)

Abstract Activation of the MET/HGF pathway has been linked to tumor initiation, metastasis, angiogenesis and resistance to therapeutic agents. Here we present pharmacological characterization of OMO-1 (formerly JNJ-38877618), a potent, highly selective, orally bioavailable MET kinase inhibitor with nM binding affinity (Kd=1.4 nM) and enzyme inhibitory activity against wt and M1268T mutant MET (2 and 3 nM IC50). MET inhibitory effects were assessed in proliferation, colony formation and motility assays. OMO-1 displayed nM potency against MET Ampl/mutant and therapy resistant models. In vivo, OMO-1 induced complete inhibition of tumor growth in 3 models: the SNU5 MET amp gastric, U87-MG HGF autocrine glioblastoma and Hs746T MET exon 14 skipping mutant gastric cancer. OMO-1 induced regression of large MET amplified EBC-1 SqNSCLC where OMO-1 led to dose- and time-dependent inhibition of MET kinase activation, with the duration of target shut down considerably exceeding plasma exposure times. Combination treatments were well tolerated and improved EGFR targeted therapy. Although single agent OMO-1 had no effect on NSCLC HCC827 EGFR, combination with Erlotinib led to delayed onset of tumor recurrence. The acquired EGFR inhibitor resistant model HCC827-ER1 was determined to be MET amplified. OMO-1 and erlotinib both inhibited tumor growth of this model whilst combination induced tumor regression. In an EGFR inhibitor resistant PDX having MET amplification, single agent OMO-1 caused tumour stasis whereas MetMab/erlotinib only led to tumor growth delay. The potent preclinical activity we have observed, supports ongoing clinical development of OMO-1 in patients with MET pathway-driven tumors. Citation Format: Marion Libouban, Eleonora Jovcehva, Desiree De Lange, Boudewijn Janssens, Tinne Verhulst, Souichi Ogata, Berthold Wroblowski, Laurence Mevellec, Tianbao Lu, Glen Clack, Timothy Perera. OMO-1, a potent, highly selective, orally bioavailable, MET kinase inhibitor with a favorable preclinical toxicity profile, shows both monotherapy activity, against MET pathway-driven tumors, and EGFR TKI combination activity in acquired resistance 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 4791.
Abstract 3922: Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells
Authors: Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka
Journal: Cancer Research (2018)

Abstract Purpose: Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the standard first-line treatment of advanced non-small cell lung cancer (NCSLC). However, almost all patients eventually acquire resistance to EGFR-TKIs, and novel therapeutic strategies to overcome the acquired resistance have been required. Heat-shock protein 90 (Hsp90) is a chaperon protein involved in folding and stabilization of client proteins essential for cancer cell growth and survival. Ganetespib (STA-9090) is one of the second-generation Hsp90 inhibitors with strong anti-tumor effect on NSCLC cells. In this study, we evaluated the anti-tumor effect of ganetespib in EGFR-TKI sensitive and acquired resistance NSCLC cell lines. Materials and Methods: We treated 4 EGFR-mutant NSCLC cell lines (HCC827, HCC4006, PC-9 and HCC4011), and 14 experimentally established EGFR-TKIs (gefitinib or afatinib) resistance cell lines with ganetespib. The EGFR-TKI resistance mechanism consisted of EGFR T790M second mutation, MET amplification, epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like features. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathways. Results: The IC50 values in parental NSCLC cell lines ranged from 1.3nM to 15nM, and those in acquired EGFR-TKI resistant cell lines ranged from 0.87nM to 25nM, which suggests strong anti-tumor effect of ganetespib. In addition, this effect was observed regardless of the resistant mechanisms, including EMT. Ganetespib suppressed EGFR activation in EGFR-TKI resistance cells harboring EGFR T790M second mutation. Also, ganetespib suppressed MET activation in EGFR-TKI resistance cells harboring MET amplification. Conclusion: Ganetespib showed strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells regardless of the resistant mechanisms, suggesting that ganetespib could be a promising therapeutic option in the treatment of NSCLC with acquired EGFR-TKI resistance. Citation Format: Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka. Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC 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 3922.
Abstract 17821: Night Time In-hospital Cardiac Arrest Impairs Good Neurological Survival in a Swiss Teaching Hospital
Authors: Luca Marengo, Wolfgang Ummenhofer, Pascal Gerster, Falko Harm, Marc Lüthy, Mathias Zürcher
Journal: Circulation (2015)

Introduction: Cardiac arrests (CA) occurring at night have been shown to be associated with lower survival rates for both out-of-hospital and in-hospital resuscitation. There is only scarce information available for Switzerland. We monitored “Rapid Response Team” (RRT) missions at our teaching hospital after implementation of the AHA 2010 guidelines. Survival data for in-hospital cardiac arrest (IHCA) were investigated depending whether the event occurred during the day or at night. Methods: A standardized extended in-hospital Utstein data set of all RRT-interventions at the University Hospital Basel, Switzerland, from December 13, 2010 until March 31, 2015 was consecutively collected and recorded in Microsoft Excel (Microsoft Corp., USA). Data were analyzed using IBM SPSS Statistics 22.0 (IBM Corp., USA) and are presented as descriptive statistics. Results: RRT was activated for 636 patients, with 459 having a life-threatening status (72%; 33 missing). 270 patients (59%) suffered IHCA. 92 CAs (34%) occurred during the night-shift (23:00 - 06:59), and 177 CAs (66%) occurred during day-shifts (07:00 - 22:59; 1 case with “time data” missing). Shockable rhythms and witnessed CA were found more often at day- compared with night-time: 34 (20%) vs. 8 (9%; p=0.032) and 133 (77%) vs. 55 (62%; p=0.009), respectively. There was no difference between day and night regarding first-responder chest compressions before RRT arrival. Patients whose IHCA occurred during the day showed more favorable neurological outcomes (Cerebral Performance Categories (CPC) of 1+2: 47 (28%) vs. 15 (17%; p=0.048)). Return of spontaneous circulation (ROSC) and hospital discharge were not different. The time to reach the CA patient was not different (123 s for first responder, 245 s for the complete team). Conclusions: IHCA occurring at night show a less favorable neurological outcome than during day time at a Swiss university hospital. A lower rate of shockable rhythms may be a sign of delayed recognition of CA during nighttime, which may be an explanation for the reduced CPC-score.
Cell Cycle in Vasculoproliferative Diseases
Authors: VissaSriram, CamPatterson
Journal: Circulation (2001)

Abstract—Atherosclerosis and restenosis of epicardial vessels are among the greatest challenges facing the clinical cardiologist, and phenotypic modulation and proliferation of smooth muscle cells are major components of the vasculoproliferative response. Proliferation is regulated by the interplay of regulatory proteins at checkpoints in the cell cycle that alter cellular growth. Activation of the cell cycle and the genetic control of its progression are final common pathways in this process. Investigators have postulated that cell-cycle inhibition using drugs and genetic or physical methods has the potential to reverse or prevent the vasculoproliferative process. The current challenge is to translate in vitro data demonstrating the efficacy of cell-cycle inhibition to clinical trials. At present, the steps that must be taken to meet this goal are (1) to design methods of delivery of these agents to specific sites, (2) to identify appropriate cellular targets to elicit cell-cycle arrest, and (3) to impro...
Abstract 4017: Inhibition of mutagenicity of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)by Chinese medicinal herbs <i>Scutellaria barbata</i> and <i>Oldenlandia diffusa</i>
Authors: Rayford Alva, Brian Yuen Yau Wong, John Tanner, Yanlingxue Wan, Padma Tadi Uppala, Ryan Hayes
Journal: Cancer Research (2018)

Abstract Scutellaria barbata (SB) and Oldenlandia diffusa (OD) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors. Recent research revealed that these two herbs were included in most of the herbal cancer treatment formulas in Taiwan hospitals. We previously showed that SB and OD inhibited mutagenesis, DNA binding and metabolism of aflatoxin B1 (AFB1) and benzo(a)pyrene (BaP) bioactivated by Aroclor 1254-induced rat S9. PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is produced from high cooking temperature of creatine, sugars, and amino acids. It was demonstrated positive result in the Ames mutagenicity test. PhIP is one of the most abundant heterocyclic amines (HCAs) in cooked meat and has been announced as "reasonably anticipated to be a human carcinogen" by the U.S. Department of Health and Human Services National Toxicology Program. Cancer of the prostate, breast, lung, esophagus, stomach, and colorectum may be related to high intake and high exposure to PhIP. In this study, the effects of aqueous extracts of SB and OD on PhIP-induced mutagenesis using Salmonella typhimurium TA98 as the bacterial tester strain and rat liver 9000 x g supernatant (S9) as the metabolic activation system were assessed. Our results showed that SB and OD significantly inhibited the mutagenicity of PhIP (both 0.1 and 1µg/plate) bioactivated by S9 (800 mg/plate) in a dose-response fashion (p&amp;lt; 0.05). The percent inhibition of revertants formation of these two herbs against 0.1µg/plate of PhIP were 45%, 77%, and 87% for SB (1.5, 3, and 6 mg/plate) and 21%, 80%, and 95% for OD (1.5, 3, and 6 mg/plate), while the percent inhibition against 1 µg/plate of PhIP were similar to that of the 0.1 µg/plate (45%, 80%, 90% for SB and 44%, 81%, 93% for OD, respectively). There was a slight additive inhibition effect of the herbs in combination (SB + OD) at higher concentrations (60%, 85%, and 90%) against both concentrations of PhIP. These results suggested that OD and SB contain antimutagenic phytochemicals towards PhIP-induced mutagenicity. Further study of their modulation effects on metabolism and DNA binding of PhIP is warranted to reveal the potential anti-mutagenicity mechanism and their chemopreventive property against PhIP and potentially against other HCAs. Citation Format: Rayford Alva, Brian Yuen Yau Wong, John Tanner, Yanlingxue Wan, Padma Tadi Uppala, Ryan Hayes. Inhibition of mutagenicity of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)by Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa [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 4017.
Abstract 5144: Cooperative effects of mushroom polysaccharides and herbal saponins on tumor growth and gut microenvironment in ApcMin/+mice
Authors: Xiao-ang Li, Guoxin Huang Huang, Imran Khan, Wen-rui Xia, Wai kit Leong, W.L. Wendy Hsiao
Journal: Cancer Research (2018)

Abstract Prebiotics are considered as non-digestible food ingredients that stimulate the growth of beneficial gut bacteria, thus contribute to the health of the host. Recent evidences have suggested that prebiotics treatment may become one of the key therapeutic strategies for many diseases, especially for cancer. In our previous studies, both Gynostemma pentaphyllum saponin (GpS) and Ganoderma lucidum polysaccharides (GlP) demonstrated significant prebiotic effects in mouse models. In addition, GpS alone exerted significant anti-tumor effect by restoring the dysbiosis of the gut microbiota and microenvironment of the ApcMin/+mice. Thus, we hypothesized that supplement with GlP might enhance the anti-cancer effect of GpS through the modulation of the gut microbiota. To test the hypothesis, we treated ApcMin/+mice with four different treatments, i.e. GlP (750mg/kg), GpS (300mg/kg), GlP (750mg/kg) + GpS (300mg/kg) and the drinking water control. The results showed that GlP+GpS was more effective in suppressing the polyp growth compared to the GpS or GlP groups. GlP+GpS also improved the health of gut barriers by inducing Paneth cells and goblet cells, and reinstating the E-cadherin and N-cadherin expressions in a greater extend compared to the other groups. All treatments facilitated the polarization of M1 macrophage to M2 macrophage, and increased the anti-inflammatory cytokines (IL-4 and IL-10). Interestingly, expressions the SCFA receptors, GPR 43, 49 and 119 were markedly elevated in all treatment groups, with the most prominent expression observed in the GlP+GpS group. 16S rRNA sequencing data were analyzed by using alpha diversity analysis and weighted UniFrac distance analysis. Differential alterations of the composition of gut microbiota were observed in all treatment groups. Certain bacteria (Anoerodtipe, Bacteroides, Clostridium, Citribacter, Subdoligranulum, C. leptum) associated colitis and colorectal carcinoma were significant decreased, while some SCFA-producing bacteria (Blautia sp., Eubacterium saphenum, Clostridium aminobutyricum) were enhanced in the treated groups. We concluded that the anti-tumor effects of GpS and GlP might be in part through the modulation of the gut microbiota and the improvement of epithelial microenvironment, and the stronger effects were produced by the GpS+ GlP combined treatment. [This study was supported by Macau FDCT 015/2014/A1 and 103/2016/A3] Citation Format: Xiao-ang Li, Guoxin Huang Huang, Imran Khan, Wen-rui Xia, Wai kit Leong, W.L. Wendy Hsiao. Cooperative effects of mushroom polysaccharides and herbal saponins on tumor growth and gut microenvironment in ApcMin/+mice [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 5144.
Role of Apoptosis in the Disappearance of Infiltrated and Proliferated Interstitial Cells After Myocardial Infarction
Authors: GenzouTakemura, MichiyaOhno, YukihiroHayakawa, JunMisao, MotooKanoh, AtsukoOhno, YoshihiroUno, ShinyaMinatoguchi, TakakoFujiwara, HisayoshiFujiwara
Journal: Circulation Research (1998)

Abstract—Myocardial infarction (MI) progresses from the acute death of myocytes and the infiltration of inflammatory cells into granulation, followed by scars. During the healing process, the myocardial interstitial cell population in the infarcted tissues increases markedly and then decreases. We postulated that apoptosis is responsible for this process. Twenty-four male Japanese white rabbits underwent a 30-minute occlusion of the left coronary artery followed by reperfusion for 2 days, 2 weeks, or 4 weeks (n=8 each). The histological features consisted of dead cardiomyocytes and marked leukocyte infiltration at 2 days after MI and granulation consisting of numerous α-smooth muscle actin–positive myofibroblasts, macrophage antigen–positive macrophages, and neovascularization at 2 weeks. At 4 weeks, the cellularity decreased markedly, and scars were evident. Interstitial cells with positive nick end labeling were significantly more frequent at the light microscopic level in the 2-day MI samples (5.3±3.6%...
Abstract 2842: The biological effects and therapeutic potential of directly targeting K-Ras
Authors: Andrew L. Wolfe
Journal: Cancer Research (2018)

Abstract K-Ras is a small GTPase that is among the most frequently mutated oncoproteins in cancer, with alterations common in lung adenocarcinoma, colorectal cancer, and up to 90% of pancreatic cancers. Tumors with mutant K-Ras often become addicted to its presence and in inducible genetic mouse models the sudden removal of mutant K-Ras can trigger cancer regressions. However, these cancers remain among the most refractory to therapy and pharmacological agents capable of inhibiting many common K-Ras mutants have remained elusive. Here, we set out to evaluate the efficacy of recently developed inhibitors that directly target K-Ras in cancer and understand potential mechanisms of resistance to K-Ras based therapies. Treatment of K-Ras mutant cells with K-Ras inhibitors led to mutant-specific halting of cell growth. Upon extended treatment a subpopulation of drug-resistant cells emerged that displayed adaptation patterns leading to reversible drug resistance. To identify cooperating factors that modulate sensitivity to K-Ras inhibition, screens were performed in wild-type and isogenic K-Ras mutant cells using a genome-wide CRISPRi library and a pharmacological compound library in the presence or absence of K-Ras inhibitors. These strategies identified synthetically lethal pathways and favorable combination therapies, moving toward the goals of identifying the optimal patient populations that can most benefit from K-Ras inhibitors and enabling a personalized medicine approach to cancer therapy. Citation Format: Andrew L. Wolfe. The biological effects and therapeutic potential of directly targeting K-Ras [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 2842.
Abstract LB-260: Development and validation of propeptide therapeutics for treating bone metastatic prostate cancer
Authors: Janelle W. Salameh, Charles S. Umbaugh, Marxa L. Figueiredo
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Most prostate cancer related fatalities are not due to tumors at origination sites, but rather due to prostate cancer metastasis throughout the body. Although the relative 5-year survival rate for localized prostate cancer nears 100%, unfortunately, upon metastasis the 5-year survival rate drops to 29.8%. Bone metastases disrupt tissue homeostasis and weaken the skeleton, resulting in an increased risk of severe bone pain and fracture. This is due to increased formation of immature unmineralized bone by osteoblasts, and increased osteolysis by osteoclasts, which induce high levels of bone resorption. Thus, a primary therapeutic objective for malignant bone disease is to eliminate tumors while promoting bone homeostasis. Current therapies are very limited and include palliative radiotherapy, and biphosphate or anti-RANK treatments, which target osteoclasts and decrease the rate of bone resorption. However, these treatments only delay, but do not prevent, skeletal related injuries. Our laboratory has recently developed a strategy aimed at disrupting malignant cytokines signals using inhibitory peptides targeting IL-6 receptors. I here present a novel strategy to express these peptides in vivo following gene delivery as targeted and multifunctional “propeptides.” These propeptides target bone metastases via EGFR antagonist (tumor-homing peptide) and contain dual therapeutic domains consistent of IL-6Ra antagonistic peptides and a pro-osteogenesis peptide, osteostatin. The propeptides are activated by metalloproteases (MMP2/9), which are overexpressed in metastatic prostate tumors and associated bone lesions. We can detect expression of the propeptides following C2C12 muscle cell transfection via real time quantitative PCR and are currently optimizing biochemical strategies for detecting propeptide products via western blot. We hypothesize that optimized secretion and targeting of the therapeutic propeptides will be effective in eliminating prostate tumor metastases, and restoring bone homeostasis. Future studies will examine the expression of propeptide in vivo following gene delivery to muscle and efficacy of propeptides in treating bone metastatic prostate tumors in a TRAMP-C2Ras tibial implantation model. Citation Format: Janelle W. Salameh, Charles S. Umbaugh, Marxa L. Figueiredo. Development and validation of propeptide therapeutics for treating bone metastatic prostate 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-260.
Transcriptional Regulation of Vascular Development
Authors: PeterOettgen
Journal: Circulation Research (2001)

Vascular development is a highly organized sequence of events that requires the correct spatial and temporal expression of specific sets of genes leading to the development of a primary vascular network. The first step in this process is the differentiation of pluripotent stem cells into endothelial cells. This is followed by endothelial proliferation, migration, and eventual formation of endothelial tubes. Maturation of these primitive tubes into fully developed blood vessels requires the recruitment of surrounding pericytes and their differentiation into vascular smooth muscle cells. Many of the events that occur during vasculogenesis are recapitulated during angiogenesis. Transcription factors have been shown to serve as master switches for regulating a number of developmental processes. Using a candidate gene approach, the genomic regulatory regions required to direct vascular-specific gene expression of several receptor tyrosine kinases that are critical for vasculogenesis have been characterized and...
Smooth Muscle Cells in Transplant Atherosclerotic Lesions Are Originated From Recipients, but Not Bone Marrow Progenitor Cells
Authors: YanhuaHu, FergusDavison, BurkhardLudewig, MartinErdel, ManuelMayr, ManfredUrl, HermannDietrich, QingboXu
Journal: Circulation (2002)

Background— Smooth muscle cell (SMC) accumulation in the intima of vessels is a key event in the pathogenesis of transplant atherosclerosis. The traditional hypothesis that SMCs in the lesion are derived from the media of the donor vessel has been challenged by recent observations, but the cell origin is still not well established. Methods and Results— Here, we use a simplified model of artery allografts in transgenic mice to clearly identify the source of SMCs in transplant atherosclerosis. Aortic segments donated by BALB/c mice allografted to ROSA26 (C57B/6) mice expressing β-galactosidase (gal) in all tissues showed that neointimal cells derived exclusively from host cells. It was also demonstrated that SMCs of neointimal and atherosclerotic lesions in vessels allografted to mice expressing β-gal only in SMCs (SM-LacZ) or to apoE-deficient/SM-LacZ mice originated from the recipient, and not donor vessels. Interestingly, bone marrow transplantation of SM-LacZ β-gal–expressing cells into aortic allograft...