tbuckley/cabot-search huggingface dataset:
Abstract 275: Flavokawain B, a kava chalcone, acts synergistically with proteasome inhibitors (i.e., bortezomib and MG132) to reduce the growth of prostate cancer cells via downregulation of Skp2
Authors: Xuesen Li, Victor Pham, Matthew Tippin, Shan Xu, Dongjun Fu, Liankun Song, Bang H. Hoang, Xiaolin Zi
Journal: Cancer Research (2018)

Abstract Flavokawain B, a chalcone isolated from kava root extracts, has been shown to inhibit the in vitro and in vivo growth of various cancer cell lines via induction of apoptosis. However, the mechanism of flavokawain B's action remains largely unknown. Here we have demonstrated that flavokawain B caused Skp2 degradation in an ubiquitin and proteasome dependent manner. In addition, flavokawain B inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Overexpression of dominant-negative cullin1 (1-452) or K720R mutant cullin1 rescued the effect of flavokawain B on Skp2 degradation, but further increased the expression of p27. However, siRNA knock-down of Skp1, CSN5, and UBC12 expression resulted in down-regulation of Skp2 expression and further enhanced the effect of flavokawain B on Skp2 degradation. siRNA knock-down of Cdh1, a known E3 ligase of Skp2 for targeted degradation, also didn't rescue the effect of flavokawain B on Skp2 degradation, but overexpression of F-box deleted Skp2 can reverse the effect of flavokawain B on Skp2 degradation. These results suggest that degradation of Skp2 by flavokawain B is involved in Cullin1. Furthermore, flavokawain B selectively inhibited the growth of pRb deficient cell lines and PC3 cells with Skp2 overexpression. Flavokawain B also acts synergistically with Bortezomib and MG132 to inhibit the growth of prostate cancer cell lines via down-regulation of Skp2 and up-regulation of p27 and p21 expression. These finding provide rationale for combination of flavokawain B and Bortezomib in treatment of prostate cancer. Citation Format: Xuesen Li, Victor Pham, Matthew Tippin, Shan Xu, Dongjun Fu, Liankun Song, Bang H. Hoang, Xiaolin Zi. Flavokawain B, a kava chalcone, acts synergistically with proteasome inhibitors (i.e., bortezomib and MG132) to reduce the growth of prostate cancer cells via downregulation of Skp2 [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 275.
Abstract 4913: A PK/PD model quantitatively describes inhibition and down-regulation of p90RSK by ERK inhibitor AZD0364
Authors: Francis D. Gibbons, Linda Sandin, Lyndsey Hanson, Rebecca Whiteley, Paul Farrington, Nicola Lindsay, Emma Davies, J Elizabeth Pease, Vikki Flemington
Journal: Cancer Research (2018)

Abstract ERK1/2 is a key protein in the MAPK pathway, regulating phenotypes such as proliferation and migration. Upstream mutations (e.g., KRAS mutations in non-small-cell lung (NSCLC)) can cause the pathway to become constitutively activated, driving tumor growth. AZD0364 is a potent, selective inhibitor of ERK's kinase activity against its cytosolic substrate p90RSK. It is currently in preclinical development, where it has shown dose-dependent, anti-tumor activity in xenograft models of KRAS-mutant NSCLC, including Calu-6 (where it shows regression) and A549. Treatment with AZD0364 demonstrates rapid and near-complete inhibition of phospho-p90RSK. In addition, prolonged inhibition with AZD0364 causes a gradual downregulation of p90RSK protein over time, without any corresponding change in p90RSK mRNA. Here we present a pharmacokinetic/pharmacodynamic (PK/PD) model that links AZD0364 concentration to inhibition of ERK activity through both a direct inhibition of phospho-p90RSK and an indirect down-regulation of total-p90RSK protein. Anti-proliferative and pro-apoptotic effects on efficacy are linked to changes in p90RSK. The model leads to two key implications (i) repeated dosing will cause apparent potency to improve over time, since the pool of available substrate (i.e., p90RSK) is itself being reduced and (ii) recovery of signaling to baseline will depend not on washout of the inhibitor but on protein synthesis rates. Protein half-lives appear quite different between tumor models of KRAS-mutant NSCLC, with A549 (~20h) significantly slower than Calu-6 (~4h). The model provides a conceptual framework on which to link the timescale of PD changes with those seen in efficacy. Taken together, this means that while a new PD steady-state is achieved in Calu-6 in a few days, it also recovers quickly, necessitating constant cover (daily dosing) to drive regression. On the other hand, while A549 is more robust to inhibition, and slower to reach steady-state inhibition (~2 weeks), it is also slower to recover, so that intermittent schedules can achieve efficacy similar to those achievable with daily dosing. Citation Format: Francis D. Gibbons, Linda Sandin, Lyndsey Hanson, Rebecca Whiteley, Paul Farrington, Nicola Lindsay, Emma Davies, J Elizabeth Pease, Vikki Flemington. A PK/PD model quantitatively describes inhibition and down-regulation of p90RSK by ERK inhibitor AZD0364 [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 4913.
Analysis of anti-leukemic activity, predictive biomarker candidates, immune activation and pharmakodynamics in R/R AML and MDS in response to treatment with bemcentinib (BGB324), a first-in class selective AXL inhibitor, in a phase II open-label, multi-centre study.
Authors: Bjorn T. Gjertsen, Monica Hellesøy, Håkon Reikvam, Astrid Olsnes Kittang, David Micklem, Anthony Brown, James Lorens, Maxim Kebenko, Melanie Janning, Mascha Binder, Walter M. Fiedler, Jorge E. Cortes, Michael Heuser, Jörg Chromik, Peter Paschka, Carlos Enrique Vigil, Sonja Loges
Journal: Journal of Clinical Oncology (2018)

7020 Background: Bemcentinib (BGB324) is a first-in-class, oral selective inhibitor of the RTK AXL currently in ph II clinical development across several cancer types. AXL overexpression has been established as an independent negative prognostic factor in AML whereas AXL inhibition via bemcentinib has shown anti-leukemic activity and immune activation in pre-clinical models of AML and other cancers. Methods: N = 35 R/R AML or MDS (interm-2 and high-risk) pts received bemcentinib monotherapy in this two part 3+3 dose escalation and cohort expansion study. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in a selection of pts pre-dose and at C2D1. Gene expression analysis was carried out by qPCR using TaqMan. Phosphorylation of AXL and downstream targets PLCγ1, Erk/MapK and Akt was carried out by single cell flow and mass cytometry. Clonal evolution was analysed by exome sequencing and TruSight myeloid panel. The TCRb- and IGH-repertoire was investigated using Biomed TCRb-A/B and Biomed2 FR-2/3 primer pools and NGS on an Illumina MiSeq platform. Results: Treatment was generally well-tolerated with most AEs being mild or moderate in severity. 2 pts achieved complete responses with incomplete recovery of peripheral counts (CRi) and 5 achieved partial responses (PR). 8 pts reported disease stabilisation for more than 4 months. Levels of plasma soluble AXL and angiogenin and BM SLFN-11 expression correlated with pt benefit. Whole exome sequencing analysis showed conservation of clones which may limit the evolution of resistant blasts. Immune activation was observed by T- and B-cell receptor diversification. PhosphoFlow analysis of AXL and downstream signalling intermediates evidenced target inhibition. Conclusions: Bemcentinib is well tolerated in MDS and AML pts and exhibits anti-leukemic activity through multiple mechanisms including immune modulation. Pt benefit (CRi/PR/SD > 4 mths) is predictable by measurement of plasma markers soluble AXL and angiogenin. Clinical trial information: NCT02488408.
Abstract 4383: CD44s is a crucial ATG7 downstream regulator for formation of sphere, a key stem-like property, invasion and lung metastasis of human bladder cancer/BC cells
Authors: Xiaohui Hua, Xun Che, Jiheng Xu, Chuanshu Huang, Grace Huang, Wei Dai
Journal: Cancer Research (2018)

Abstract Over half a million US residents are suffering with bladder cancer (BC), which costs a total $4 billion in treatment annually. Although recent studies report that autophagy-related gene 7 (ATG7) is overexpressed in BCs, the regulatory effects of ATG7 on stem-like phenotypes and invasion have not been explored yet. Current studies demonstrated that the deficiency of ATG7 by its specific shRNA dramatically reduced Sphere formation and invasion in vitro, as well as lung metastasis in vivo in invasive BC cells. Further studies indicated that the knockdown of ATG7 attenuated the expression of CD44 and CD133, while ectopic introduction of CD44s, but not CD133, was capable of completely restoring sphere formation, invasion, and lung metastasis in T24T(shATG7) cells. Mechanistic studies revealed that ATG7 overexpression stabilized CD44s proteins accompanied with upregulating USP28 proteins. Upregulated USP28 was able to bind to CD44s and remove the ubiquitin group from CD44's protein, resulting in the stabilization of CD44s protein. Moreover, inhibition of ATG7 stabilized AUF1 protein and in turn reduced tet1 mRNA stability and expression, which was able to demethylate usp28 promoter, thereby reduced USP28 expression, finally promoting CD44s degradation. In addition, CD44s was defined to inhibit degradation of RhoGDIβ, which in turn promotes BC invasion. Our results demonstrate that CD44s is a key ATG7 downstream regulator of the sphere formation, invasion, and metastasis of BCs, providing significant insight into understanding the BC invasions, metastasis, and stem-like properties. Citation Format: Xiaohui Hua, Xun Che, Jiheng Xu, Chuanshu Huang, Grace Huang, Wei Dai. CD44s is a crucial ATG7 downstream regulator for formation of sphere, a key stem-like property, invasion and lung metastasis of human bladder cancer/BC 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 4383.
Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab
Authors: David R. Gandara, Sarah M. Paul, Marcin Kowanetz, Erica Schleifman, Wei Zou, Yan Li, Achim Rittmeyer, Louis Fehrenbacher, Geoff Otto, Christine Malboeuf, Daniel S. Lieber, Doron Lipson, Jacob Silterra, Lukas Amler, Todd Riehl, Craig A. Cummings, Priti S. Hegde, Alan Sandler, Marcus Ballinger, David Fabrizio, Tony Mok, David S. Shames
Journal: Nature Medicine (2018)
Abstract 1100: Screening the chemical library against granulocytic MDSCs: Critical player in breast cancer metastasis
Authors: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Thomas Albers, Maria Ouzounova, Charlie Weeks, Riley Rodier, Ahmet K. Korkaya, Khaled A. Hassan
Journal: Cancer Research (2018)

Abstract We recently demonstrated that infiltration of granulocytic MDSCs in distant organs is a critical step in metastatic process. The mouse transcriptome analysis of in vitro co-cultures and samples from syngeneic mouse model revealed that granulocytic subset of myeloid-derived suppressor cells (gMDSCs) from metastatic 4T1 tumor bearing mice are regulated a distinct set of genes. Two genes, S100A8 and S100A9 were highly upregulated in gMDSCs isolated from mice with metastatic 4T1 tumors compared to mice with non-invasive tumors. Using the recombinant single S100A8, S100A9 proteins or the S100A8/S100A9 heterotetramer (calprotectin), we demonstrated that calprotectin is a critical player in gMDSC induction and infiltration in distant organs particularly in lungs. Furthermore, injection of recombinant calprotectin but not single S100A8 or S100A9 proteins via tail vein enhanced the metastatic ability of nan-invasive EMT6 tumors in mice. We therefore performed computational screen of NCI compounds against the crystal structure of calprotectin and identified over 100 lead compounds. In vitro gMDSC differentiation assay identified 3 compounds with strong gMDSC inhibitory activity. We therefore designed a pilot experiment to test these compounds in preclinical mouse models. We also compared the activity of these compounds against tasquinimod, a small molecule targeting S100A9 only. However, tasquinimod treatment of 4T1 tumor-bearing mice had a moderate anti-tumor activity which may be due to a limited activity on granulocytic MDSC accumulation. In addition, we determined that there was a significant upregulation of S100A8 in MDSCs from tasquinimod treated mice. This data suggested that inhibiting only S100A9 leads to activation of S100A8 and thus may be ineffective targeting of MDSCs. In line with these data, one of the compounds (#10) showed a potent activity against gMDSCs in 4T1 tumor-bearing mice and significantly inhibited pulmonary metastasis. Moreover, this compound eliminated the cytotoxicity caused by cyclophosphamide and animals were free of cancer. In summary, we have identified a molecular target which regulates gMDSC induction and play critical role in metastatic process and our findings from in vitro screens and preclinical testing provide a strong rationale for targeting MDSCs. Citation Format: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Thomas Albers, Maria Ouzounova, Charlie Weeks, Riley Rodier, Ahmet K. Korkaya, Khaled A. Hassan. Screening the chemical library against granulocytic MDSCs: Critical player in breast cancer metastasis [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 1100.
Predictive Value of D-Dimer Test for Recurrent Venous Thromboembolism After Anticoagulation Withdrawal in Subjects With a Previous Idiopathic Event and in Carriers of Congenital Thrombophilia
Authors: GualtieroPalareti, CristinaLegnani, BenildeCosmi, LeliaValdré, BarbaraLunghi, FrancescoBernardi, SergioCoccheri
Journal: Circulation (2003)

Background— We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not. Methods and Results— We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurre...
Origin of Respiratory Sinus Arrhythmia in Conscious Humans
Authors: MassimoPiepoli, PeterSleight, StefanoLeuzzi, FeliceValle, GiammarioSpadacini, ClaudioPassino, JimJohnston, LucianoBernardi
Journal: Circulation (1997)

Background We investigated whether respiratory sinus arrhythmia (RSA) in healthy humans originated from central neuronal oscillations or from peripheral baroreceptors responding to respiratory changes in venous return. Methods and Results During subjects’ controlled breathing we used sinusoidal neck suction to influence RSA (spectral analysis of RR interval). In 11 subjects, 20-second apnea greatly reduced RSA, which was restored by neck suction at the frequency of respiration. Counteracting the respiration-induced cycles of carotid blood pressure decreased RSA in 13 subjects (from 2136±682 to 1372±561 ms2, P<.01). The critical phase of this neck suction was constant for each subject at around the phase shift (with regard to respiration-related fluctuations of blood pressure) best for smoothing respiratory (mechanical) changes in blood pressure. Suction of a nonbaroreceptor area (the thigh) did not affect RSA. In 4 subjects, to separate the effects of peripheral baroreceptor afferents from respiration-ent...
Abstract 2517: The role of endocytic traffic regulator EHD1 in EGFR traffic and breast cancer
Authors: Insha Mushtaq, Eric C. Tom, Priyanka Arya, Timothy Bielecki, Bhopal Mohapatra, Sameer Mirza, Matthew D. Storck, Dena Ahmad, Rokaya El Ansari, Emad Rakha, Vimla Band, Hamid Band
Journal: Cancer Research (2018)

Abstract Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase and serves as an oncogene in a variety of solid tumors. Its surface expression is dynamically regulated, and display of an activation-competent cell surface pool is an essential pre-requisite for cellular responses to EGF and other ligands, as well as for its oncogenic function. While mechanisms that regulate the post-activation endocytic fate of EGFR have received much attention, little is known about the mechanisms that control the basal, pre-activation, surface display of EGFR. Here, we identify a novel role of the endocytic recycling regulator EHD1 in the cell surface display of EGFR and EGF-driven functional responses. We demonstrate that inducible knockdown of EHD1 in human mammary epithelial cells impairs the EGFR delivery to the cell surface, resulting in reduced EGFR cell surface expression and accumulation in the Golgi, a phenotype rescued by exogenous EHD1. Reduced surface display of EGFR by depletion of EHD1 impaired EGF-induced proliferation mammary epithelial cells and a breast cancer cell line, demonstrating that the new molecular pathway we describe is functionally important. Given the role of EGFR and its family members in breast cancer, we carried out IHC screening of EHD1 expression in human breast cancer using tissue microarrays from a large (&amp;gt;800 samples) and well-annotated breast cancer cohort. Of the 757 evaluable samples, EHD1 was overexpressed in 115 (15%) patients. Notably, a substantially higher percentage of HER2/ErbB2+ patients (25%) showed EHD1 overexpression. Survival analysis revealed that EHD1 overexpression was associated with a significantly shorter overall survival over 15 years of follow up. These studies reveal novel roles of EHD1 in regulating EGFR traffic and suggest its potential roles in regulating other EGFR family members, especially HER2/ErbB2. Our patient sample analyses support a role for EHD1 overexpression in promoting breast tumorigenesis. Future studies will be directed at directly testing the role of EHD1, and its family members, in HER2 traffic and the role of EHD1 in breast tumorigenesis. As EHD proteins possess ATPase activity, which is required for their function, our studies raise the prospect of developing inhibitors of these enzymes as potential anti-cancer agents. Citation Format: Insha Mushtaq, Eric C. Tom, Priyanka Arya, Timothy Bielecki, Bhopal Mohapatra, Sameer Mirza, Matthew D. Storck, Dena Ahmad, Rokaya El Ansari, Emad Rakha, Vimla Band, Hamid Band. The role of endocytic traffic regulator EHD1 in EGFR traffic and 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 2517.
Atrial Septal Defect
Authors: Yu-Chenlee, Leonardscherlis
Journal: Circulation (1962)

The results of the electrocardiographic, vectorcardiographic, and hemodynamic studies of 70 patients with atrial septal defects are analyzed. Serial electrocardiograms and vectorcardiograms were obtained in 16 patients following surgery. The incidence of the rSR' and rSr' patterns in the right precordial leads was 60 per cent. To a limited extent, the configuration of the electrocardiogram is related to right ventricular pressure and PBF/SBF. However, no quantitative assessment could be made by determining the magnitude of R or R' in lead V1. The vectorcardiogram is an important adjunct to the electrocardiogram in detecting right ventricular hypertrophy. As the right ventricular pressure increases, the QRS sE loop tends to shift more to the right and anteriorly. Although it can be generally stated that the rSR' configuration in atrial septal defects is usually due to right ventricular hypertrophy, this configuration is also due to terminal conduction delay or terminal conduction delay associated with rig...
Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease
Authors: ThomasHeitzer, TitusSchlinzig, KarolineKrohn, ThomasMeinertz, ThomasMünzel
Journal: Circulation (2001)

Background Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Methods and Results Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation...
The Syndrome of Patent Ductus Arteriosus with Pulmonary Hypertension
Authors: Herberthultgren, Arthurselzer, Annpurdy, Emileholman, Frankgerbode
Journal: Circulation (1953)

Eight cases of patent ductus arteriosus associated with marked pulmonary hypertension are presented with complete cardiac catheterization studies in six patients and autopsy studies in three cases. Four patients had clear evidence of a reversed shunt through the ductus, three presenting the clinical picture of cyanotic congenital heart disease. The authors discuss the nature of the increased resistance of the pulmonary vascular bed which is the basis of the circulatory changes in these cases.