tbuckley/cabot-search huggingface dataset:
Abstract 2866: Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity
Authors: Elimelech Nesher, Albert Pinhasov, Maria Becker, Michael Kirby, Raichel Cohen Harazi, Shiri Yakobovich, Oryan Agranyoni, Bar Shoval, Shany I. Elbaz, Olga Udartseva, Ilya Gitlin, Katerina Leonova, Katerina Gurova, Andrei Gudkov, Igor Koman
Journal: Cancer Research (2018)

Abstract The association of chronic inflammation with cancer development and progression has been well recognized. Here, we report a synthetic cyclic peptide, ALOS4, capable of suppressing tumor growth following systemic administration and possessing anti-inflammatory properties. Although ALOS4 was initially isolated by phage display for its ability to bind avb3 integrin and demonstrated tumor-suppressor activity in preclinical xenograft and syngeneic models of melanoma, it surprisingly showed no functional activity resembling RGD peptides in functional in vitro assays. Remarkably, ALOS4 displayed no signs of toxicity in treated animals, even at doses exceeding &amp;gt;100-fold beyond the efficacious dose. To identify the mechanisms underlying profound antitumor activity of this safe peptide, we used a large panel of cell-based repeater assays designed to detect modulators of a variety of signaling pathways including p53, NF-kB, and different types of stress responses including heat shock and hypoxia. We also tested the effects of ALOS4 on tumor cell growth, adhesion, clonogenicity, morphology and other in vitro properties. ALOS4 showed no detectable activity in any of these numerous assays with one exception: it suppressed the ability of treated cells to induce interferon type I signaling in response to mimics of double-stranded RNA (Poly I:C). Based on this observation, we hypothesized that the antitumor effect of ALOS4 is driven by a systemic anti-inflammatory effect rather than by a direct effect on tumor cells. Consistently, ALOS4 treatment dramatically altered both the abundance and content of the immunocyte population infiltrating subcutaneous melanomas in mice. These results suggest that ALOS4 may be an anticancer agent with a new mechanism of action that targets the tumor-supporting interferon-driven mechanism of tumor-host interaction. Citation Format: Elimelech Nesher, Albert Pinhasov, Maria Becker, Michael Kirby, Raichel Cohen Harazi, Shiri Yakobovich, Oryan Agranyoni, Bar Shoval, Shany I. Elbaz, Olga Udartseva, Ilya Gitlin, Katerina Leonova, Katerina Gurova, Andrei Gudkov, Igor Koman. Anticancer effect of a new cyclic peptide ALOS4 is associated with its systemic anti-inflammatory activity [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 2866.
Shortened Head-Up Tilting Test Guided by Systolic Pressure Reductions in Neurocardiogenic Syncope
Authors: MariavittoriaPitzalis, FrancescoMassari, PietroGuida, MassimoIacoviello, FilippoMastropasqua, BrianRizzon, CinziaForleo, PaoloRizzon
Journal: Circulation (2002)

Background— Asymptomatic reductions in arterial pressure have been reported to occur before the onset of tilt-induced syncope. We investigated the predictive value of these reductions for a positive tilt result. Methods and Results— In a first study, 238 consecutive healthy subjects with unexplained syncope underwent a passive tilt table test. Finger systolic arterial pressure (SAP) recordings made it possible to calculate how many of the beat-to-beat SAP values during the first 15 minutes of tilt were lower than the lowest value recorded at baseline. Neurocardiogenic syncope was diagnosed in 73 subjects; 28 fainted after 15 minutes of tilt and experienced more pressure reductions than did the subjects with a negative test (328±400 versus 119±284; P<0.01). More than 14 SAP reductions during the first 15 minutes of tilt allowed us to predict a positive test with 93% sensitivity, 58% specificity, and positive and negative predictive values of 28% and 98%, respectively. In a second prospective study (80 cons...
H-Ras Regulates Angiogenesis and Vascular Permeability by Activation of Distinct Downstream Effectors
Authors: DoinitaSerban, JieLeng, DavidCheresh
Journal: Circulation Research (2008)

Angiogenesis and vascular permeability occur following endothelium activation by vascular endothelial growth factor (VEGF). Downstream mechanisms that define these vascular responses remain unknown. H-Ras activation has been associated with the angiogenic response. However, active H-Ras initiates a wide spectrum of other biological responses through multiple downstream effectors. To identify vascular signaling by H-Ras and the immediate effectors we activated the extracellular signal regulated kinase/mitogen-activated protein kinase or phosphatidylinositol 3-kinase (PI3K) pathways in chicken and mouse endothelial tissues by ectopic expression of the Ras effector mutants H-RasV12S35 or H-RasV12C40, respectively. Constitutive activation of the extracellular signal-regulate kinase/mitogen-activated protein kinase pathway by H-RasV12S35 was sufficient to induce angiogenesis and not vascular permeability, whereas activation of the PI3K pathway by H-RasV12C40 was required for both angiogenesis and vascular perm...
Abstract 3675: Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA)
Authors: Koichi Tomoshige, Minzhe Guo, Tomoshi Tsuchiya, Iris Fink-Baldauf, Takeshi Nagayasu, Kelsey Dillehay McKillip, Yutaka Maeda
Journal: Cancer Research (2018)

Abstract Background: Invasive mucinous adenocarcinoma of the lung (IMA) is pathologically characterized as lung tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin. IMA has been reported to account for 2-10% of lung adenocarcinomas. Genetically, the majority of IMA harbor KRAS mutations. Recently, by analyzing RNA-seq data using human IMA cases, we reported mucus-related genes specifically expressed in IMA, which includes MUC5AC, MUC5B, MUC3, SPDEF, FOXA3 and HNF4 (Guo, Tomoshige et al., 2017). Notably, immunohistochemical analyses have determined that NKX2-1 (also known as TTF-1) is reduced in IMA (Travis et al., 2011); however, other than NKX2-1, genes reduced in IMA compared to normal lungs have not been determined. Methods: In order to further understand the demographic occurrence of IMA, we surveyed the clinical records at the University of Cincinnati College of Medicine in the U.S. and Nagasaki University of School of Medicine in Japan. Genes reduced in IMA compared to normal lungs were identified using the RNA-seq datasets as we have previously reported (Guo, Tomoshige et al., 2017). Using single-cell and sorted RNA-seq datasets (LGEA; Du et al., 2017), genes were further categorized into groups that define different cell types that exist in normal lungs. Results: IMA occurred in 4.6% (3/65 cases in 2017) and 1.9% (2/105 cases in 2017) of lung adenocarcinomas at the University of Cincinnati College of Medicine and Nagasaki University of School of Medicine, respectively. Importantly, analysis using normal lung cell type specification markers obtained from the single-cell and sorted RNA-seq datasets identified that genes that define alveolar type II epithelial cells (e.g., SFTPC and ABCA3) and endothelial cells (e.g., FOXF1 and SOX17) were significantly reduced in IMA compared to normal lungs. Conclusion: IMA comprises mucus-producing goblet cell lineage populations devoid of alveolar type II epithelial and endothelial cell-lineage populations, suggesting a unique tumor microenvironment distinct from other lung adenocarcinomas. Citation Format: Koichi Tomoshige, Minzhe Guo, Tomoshi Tsuchiya, Iris Fink-Baldauf, Takeshi Nagayasu, Kelsey Dillehay McKillip, Yutaka Maeda. Loss of alveolar type II epithelial and endothelial cell lineages in invasive mucinous adenocarcinoma of the lung (IMA) [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 3675.
The Electrocardiographic Pattern of Hypopotassemia with and without Hypocalcemia
Authors: Boryssurawicz, Eugenelepeschkin
Journal: Circulation (1953)

Detailed analysis of the electrocardiogram in patients with hypopotassemia without hypocalcemia showed that the Q-U interval and its components (Q-oT, Q-aT, Q-T, and Q-aU) have essentially the same duration as in normal subjects for the same heart rate and sex. The typical hypopotassemia pattern is characterized by progressive depression of S-T, lowering and inversion of T and increase of U in left precordial leads. In hypopotassemia with hypocalcemia S-T and Q-T, but not Q-U, are prolonged, causing an increased degree of merging between T and U. Three methods of differentiation between completely merged T and U waves and true T waves of long Q-T duration are given.
Ca2+-Related Signaling and Protein Phosphorylation Abnormalities Play Central Roles in a New Experimental Model of Electrical Storm
Authors: YukiomiTsuji, MayumiHojo, NielsVoigt, AliEl-Armouche, YasuyaInden, ToyoakiMurohara, DobromirDobrev, StanleyNattel, ItsuoKodama, KaichiroKamiya
Journal: Circulation (2011)

Background—Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca2+-related protein alterations in ES. Methods and Results—We studied 37 rabbits with complete atrioventricular block for ≈80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (≥3 VF episodes per 24-hour period; 103±23 VF episodes per rabbit). Expression/phosphorylation of Ca2+-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventric...
Abstract 4760: Joint modeling of longitudinal tumor dynamics and survival in non-small cell lung cancer (NSCLC) patients
Authors: Xiao Tong, James Dunyak, Diansong Zhou, David Carlile, Helen Tomkinson, Gabriel Helmlinger, Nidal Al-Huniti, Hongmei Xu
Journal: Cancer Research (2018)

Abstract Objectives: Tumor size dynamics and survival are traditionally analyzed in a 2-stage approach, without consideration of joint dependencies. The objective of this analysis was to develop a joint model which associates tumor size dynamics and progression-free survival (PFS), to predict time-to-progression. Methods: Phase 2 trial data from selumetinib (AZD6244; ARRY-142886, MEK inhibitor), in NSCLC patients (SELECT-2; NCT01750281) were used to develop a joint model for tumor size dynamics and PFS. The analysis was performed using JM package in R. Treatment arm, KRAS mutation and WHO performance status were evaluated as covariates. Model was evaluated by survival estimation based on early time (e.g., first 3 months) tumor size data. The final joint model based on SELECT-2 data was then used to predict PFS of selumetinib in SELECT-1 (NCT01933932) phase 3 trial. Results: The joint model developed on SELECT-2 data identified a significant association (p value &amp;lt;0.001) between the slope of the longitudinal tumor dynamic and PFS. WHO performance status was identified to be the only significant covariate. Furthermore, the model built on phase 2 data adequately predicted PFS of the SELECT-1 data, using SELECT-1 tumor size data within 4 months of treatment. Prediction confirmed no significant difference in PFS between active treatment arm and chemotherapy arm in SELECT-1 trial. Conclusions: Using selumetinib as an example, we showed that joint modeling of tumor size dynamics and PFS may provide a novel quantitative tool to predict long-term outcome in NSCLC based on early tumor size measurements. Citation Format: Xiao Tong, James Dunyak, Diansong Zhou, David Carlile, Helen Tomkinson, Gabriel Helmlinger, Nidal Al-Huniti, Hongmei Xu. Joint modeling of longitudinal tumor dynamics and survival in non-small cell lung cancer (NSCLC) patients [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 4760.
Abstract 4891: Co-inhibition of AXL and FN14 by pharmacologic inhibitors or genetic inhibition in NSCLC mice models
Authors: Dhananjay Suresh, Soumavo Mukherjee, Ajit Zambre, Shreya Ghoshdastidar, Sairam Yadavilli, Anandhi Upendran, Raghuraman Kannan
Journal: Cancer Research (2018)

Abstract Non-small Cell Lung Cancer (NSCLC) patients who express EGFR activating mutations are treated with tyrosine kinase inhibitors (TKI) and have a median overall survival time of 22 months. TKI therapy showed only moderate success with poor (37%) survival rate. On the other hand, TKI therapy is ineffective in patients with active KRAS mutation. Acquired drug resistance is one of the major reasons for the failure of the TKI therapy. Studies have shown that overexpression of AXL is one of the possible reasons for the drug resistance. In our previous studies, we have shown that AXL inhibition in NSCLC drug-resistant cells resulted in FN14 survival activation. Subsequently, we have demonstrated that co-inhibition of both AXL and FN14 resulted in increased therapeutic efficacy. Based on these studies, we recognize that both AXL and FN14 play important role in proliferation, invasion and survival pathways. Therefore, synergistic co-inhibition of AXL-FN14 is a viable therapeutic strategy for treating NSCLC. In the present study, we compared the efficacy of inhibition of AXL and FN14 by siRNA (using nanoparticle delivery vehicles) and small-molecule inhibitors in A549 mouse xenografts. Our data further confirms that co-inhibition is effective and results in tumor volume reduction. The details of this study provide a rationale for enhanced treatment of drug resistant NSCLC. Citation Format: Dhananjay Suresh, Soumavo Mukherjee, Ajit Zambre, Shreya Ghoshdastidar, Sairam Yadavilli, Anandhi Upendran, Raghuraman Kannan. Co-inhibition of AXL and FN14 by pharmacologic inhibitors or genetic inhibition in NSCLC mice 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 4891.
Abstract 12852: The Incremental Value of Three-Dimensional Transesophageal Echocardiography for the Diagnostic Assessment of Infective Endocarditis
Authors: FabioChirillo, MartaPossamai, MatteoRugolotto, PaolaMartire, GiuseppeMinniti, SaraGiacomelli, PiergiorgioScotton, ElvioPolesel, ZoranOlivari
Journal: Circulation (2014)

Two-dimensional transesophageal echocardiography (2D TEE) may fail to detect signs of infective endocarditis (IE) or to delineate complex anatomic lesions due to suboptimal visualization of the infected area. Three-dimensional (3D) TEE may have additional value; however, data are scarce. In 124 consecutive patients (85 M; Mean age 63 ± 14 years) with definite IE involving the aortic (36), mitral (35), tricuspid (5), ≤ 1 valve (6), and prosthetic valves (30),or pace-maker/ICD leads (12) the comparative analysis between 2D and 3D imaging focused on: 1) Presence and maximal dimension of vegetations; 2) Prediction of embolic events; 3) Location and dimension of valve perforation; 3) Prediction of successful mitral valve repair; 4) Identification and morphologic assessment of perivalvular complications.3D TEE detected more vegetations per patient (1.9 ± 2.1 vs 1.7± 1.6; p= 0.06), but this difference was significant only for vegetations on prosthetic valves and PM/ICD leads (2.2 ± 1.7 vs 1.1 ± 1.5; p=0.03). Tom...
Angiotensin-converting enzyme and subclinical atherosclerosis in psoriasis: Is there any association? A case-control study
Authors: Fahimeh Abdollahimajd, Nasim Niknezhad, Hamid Reza Haghighatkhah, Nastaran Namazi, Nakisa Niknejad, Atefeh Talebi
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 4632: Decitabine for neuroblastoma cure: Target therapy induced ongoing acquisition of RD3 loss and reverts tumor evolution
Authors: Aravindan Natarajan, Dinesh Babu Somasundaram, Sheeja Aravindan, Mohan Natarajan, Terence Herman
Journal: Cancer Research (2018)

Abstract Recently, we defined the novel tumor evolution stabilization role of Retinal degeneration protein 3 (RD3), regulating the metastatic state of neuroblastoma (NB) cells in vitro and their metastatic potential in vivo. Our earlier studies in various tumor models recognized the role of therapy resistant residual cells in tumor recurrence and relapse. Herein, we investigated the ongoing acquisition of RD3 transcriptional regulation in radiotherapy surviving NB cells and further identified the potential drug candidates that can reprogram and reinstate RD3 transcription in these cells. Human NB (SH-SY5Y, SK-N-AS) cells exposed to single dose (10, 20, 50cGY, 1, 2, 4Gy) or fractionated (FIR, 2Gy/Day for 5 days) irradiation resulted in significant transcriptional repression of RD3. Drug screening with a panel of drugs that are in current clinical use, those in pipelines or in developmental stages by exposing radioresistant cells identified many potential drug candidates that could effectively restore RD3 transcription in this setting. Evidently, we found RD3 promoter region hypermethylation drives its transcriptional regulation in therapy resistant cells. To that note, FDA approved hypomethylating agent decitabine significantly reinforced RD3 transcription in this setting and further promoted cellular differentiation and completely inhibited the formation of organized tumorosphere under stem-cell culture conditions. Together, these results demonstrate the ongoing acquisition of RD3 loss in therapy resistant cells and further recognized the mechanism of how RD3 is regulated in this setting. More importantly, this results of this study identified a drug candidate, that has been already in clinical use, that could be beneficial in mitigating therapy resistance and better clinical outcomes for the patients presented with high-risk advanced disease. Funding: NIH-COBRE-IP20GM103639-01, OUHSC-COM-Radiation Oncology Research Development Funds Citation Format: Aravindan Natarajan, Dinesh Babu Somasundaram, Sheeja Aravindan, Mohan Natarajan, Terence Herman. Decitabine for neuroblastoma cure: Target therapy induced ongoing acquisition of RD3 loss and reverts tumor evolution [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 4632.
Abstract P040: Mst1 Physically Interacts with and Phosphorylates Beclin1, Thereby Negatively Regulating Autophagy in the Heart
Authors: YasuhiroMaejima, ShioriKyoi, PeiyongZhai, JunichiSadoshima
Journal: Circulation Research (2011)

Autophagy mediates protein degradation and participates in protein quality control (QC). Inhibition of autophagy below physiological levels induces protein aggregation and cellular dysfunction. Beclin1 is a BH3-only protein that binds to Bcl-2. Bcl-2 negatively regulates autophagy through interaction with Beclin1. Here we show that the interaction between Bcl-2 and Beclin1 is regulated by mammalian STE 20 like-kinase-1 (Mst1), a proapoptotic kinase, in the heart. In Mst1 transgenic mice (Tg-Mst1), a model of dilated cardiomyopathy, accumulation of aggresomes was significantly increased and p62/SQSTM1, a protein degraded by autophagy, accumulated markedly in the myocardium. Autophagosome formation, as evaluated by GFP-LC3 dots, was suppressed in Tg-Mst1. The activity of Mst1 was suppressed by amino acid deprivation (AD) in cultured cardiomyocytes (CMs), and restoration of Mst1 activity attenuated AD-induced autophagy, as evaluated by LC3-II/ LC3-I and accumulation of p62/SQSTM1. Mst1 inhibited the kinase a...
Ouabain Effects on Cardiac Contraction, Action Potential, and Cellular Potassium
Authors: PAULMüLLER
Journal: Circulation Research (1965)

Transmembrane potential, isometric tension, and K42 content of sheep or calf myocardial bundles were recorded simultaneously during periods up to 30 hours. Ouabain at low concentrations (1.5 x 10-8 M/L) decreased intracellular K to a new steady level which was reached after several hours. Its value depended on drug concentration. The effect was reversible. There was a striking temporal parallelism between the potassium loss and the inotropic effect which was suggestive of a close relationship between the two phenomena. Action potentials during these experiments did not change in a consistent way.
Development and evaluation of a CEACAM6-targeting theranostic nanomedicine for photoacoustic-based diagnosis and chemotherapy of metastatic cancer
Authors: Hohyeon Lee, Yongho Jang, Suhyun Park, Hyejin Jang, Eun-Joo Park, Hyun Jung Kim, Hyuncheol Kim
Journal: Theranostics (2018)

Metastasis is the leading cause of cancer-related deaths. A number of chemotherapeutic and early diagnosis strategies, including nanomedicine, have been developed to target metastatic tumor cells. However, simultaneous inhibition and imaging of metastasis is yet to be fully achieved. Methods: To overcome this limitation, we have developed human serum albumin-based nanoparticles (tHSA-NPs) with photoacoustic imaging capability, which target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). CEACAM6 is highly expressed in metastatic anoikis-resistant tumor cells. Results:In vitro, the CEACAM6-targeting tHSA-NPs efficiently targeted CEACAM6-overexpressing metastatic anoikis-resistant tumor cells. In vivo, CEACAM6-targeting tHSA-NPs administered intravenously to BALB/c nude mice efficiently inhibited lung metastasis in circulating anoikis-resistant tumor cells compared to the controls. In addition, anoikis-resistant tumor cells can be successfully detected by photoacoustic imaging, both in vitro and in vivo, using the intrinsic indocyanine green-binding affinity of albumin. Conclusion: In summary, the CEACAM6-targeting albumin-based nanoparticles allowed the delivery of drugs and photoacoustic imaging to metastatic anoikis-resistant tumor cells in vitro and in vivo. Based on the expression of CEACAM6 in a variety of tumors, CEACAM6-targeting nanomedicine might be used to target various types of metastatic tumor cells.
Abstract 12276: Favorable Cardiovascular Risk Profile at Young/Middle Ages and 39-Year Progression of Major and Minor Electrocardiographic (ECG) Abnormalities - The Chicago Healthy Aging Study (CHAS)
Authors: Thanh-Huyen T Vu, Martha Daviglus, Kiang Liu, Daniel B Garside, Donald M Lloyd-Jones
Journal: Circulation (2014)

Methods: Using data from CHAS, we assessed the association of favorable CVD risk profile, i.e., low risk (LR) at baseline (1967-73) with ECG major or minor abnormality progression 39 years later (2...