tbuckley/cabot-search huggingface dataset:
Characterization of Insulin-Like Growth Factor-1–Induced Activation of the JAK/STAT Pathway in Rat Cardiomyocytes
Authors: ToshiyukiTakahashi, KeiichiFukuda, JingPan, HiroakiKodama, MotoakiSano, ShinjiMakino, TakahiroKato, TomohiroManabe, SatoshiOgawa
Journal: Circulation Research (1999)

Abstract—This study was designed to investigate whether insulin-like growth factor-1 (IGF-1) transduces signaling through the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and to assess the upstream signals of serine and tyrosine phosphorylation of STAT family proteins. Primary cultured neonatal rat cardiomyocytes were stimulated with IGF-1 (10−8 mol/L). JAK1, but not JAK2 or Tyk2, was phosphorylated by IGF-1 as early as 2 minutes and peaked at 5 minutes. IGF-1 induced both tyrosine and serine phosphorylation of STAT1 and STAT3. Tyrosine phosphorylation of STAT1 peaked at 15 minutes and correlated with that of JAK1, whereas that of STAT3 was sustained up to 120 minutes and was dissociated from the activation of JAK1. Tyrosine phosphorylation of STAT3 was unaffected by the preincubation with CV11974 (AT1 blocker), TAK044 (endothelin-1 receptor blocker), RX435 (anti-gp130 blocking antibody), PD98058, wortmannin, EDTA, or KN62 but was significantly att...
Abstract 4573: Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system
Authors: Jessica Ventura, Pavel Lobachevsky, Jason Palazzolo, Helen Forrester, Nicole Haynes, Alesia Ivashkevich, Andrew Stevenson, Christopher Hall, Vassilis Gorgoulis, John Hamilton, Alexandros Georgakilas, Calr Sprung, Olga A. Martin
Journal: Cancer Research (2018)

Abstract The discovery of the radiation-induced bystander effect has expanded knowledge of radiobiological mechanisms of ionizing radiation. A counterpart in vivo phenomenon is the radiation-induced abscopal effect (RIAE). It is not known how radiation settings affect non-targeted normal tissues and therefore the risk of adverse RIAE. At the Australian Synchrotron we examined systemic effects of microbeam radiotherapy (MRT) and broad beam (BB) configurations, in mice that were locally exposed to a very short pulse of a high dose-rate synchrotron beam (49 Gy/sec). We determined how radiation volume and dose impact the RIAE. C57BL/6 mice were irradiated with 10 or 40 Gy incident dose of MRT or BB in an 8x8, 8x1, or 2x2-mm area of the right hind leg. Blood samples, irradiated skin and a variety of normal unirradiated tissues were collected for DNA damage analysis of double-strand breaks (DSBs) quantified as gamma-H2AX foci and oxidatitive clustered DNA lesions (OCDL). OCDLs elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, a trend for elevated apoptotic cells was observed, however DSBs elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in concentrations of MDC, CCL2/MCP1, Eotaxin, IL-10, TIMP-1, VEGF, TGFβ-1 and TGFβ-2 plasma cytokines and by changes in frequencies of macrophages, neutrophils and T-lymphocytes in duodenum. Overall, systemic radiation responses were dose-independent (1). The MRT irradiations was repeated in immune-deficient mice: NSG, CCL2 knock-outs, and in C57BL/6 mice treated with anti-CSF1R antibody which effectively depletes macrophages. Strikingly, these effects and the abscopal innate and adaptive immune effector responses were completely or partially abrogated in the mice with various immune deficiencies, highlighting the role of the functional immune system in propagation of systemic genotoxic effects of radiation. These findings have implications for the planning of therapeutic and diagnostic radiation to reduce the risk of radiation-related adverse systemic effects. 1. Ventura et al, Cancer Research, e-pub (2017). Citation Format: Jessica Ventura, Pavel Lobachevsky, Jason Palazzolo, Helen Forrester, Nicole Haynes, Alesia Ivashkevich, Andrew Stevenson, Christopher Hall, Vassilis Gorgoulis, John Hamilton, Alexandros Georgakilas, Calr Sprung, Olga A. Martin. Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system [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 4573.
Abstract 4058: Race-associated breast cancer disparities: The role of CRYBB2 and its pseudogene
Authors: Maya A. Barrow, Megan E. Martin, Denise K. Reaves, Breanna Jeffcoat, Ginger R. Smith, Michael Tarpley, Kevin P. Williams, Jodie M. Fleming
Journal: Cancer Research (2018)

Abstract Research demonstrates young African American (AA) women have higher mortality rates for triple-negative breast cancer (TNBC), despite lower incidence rates, when compared to Caucasian American (CA) women. These disparate poor patient outcomes may be attributed to access to quality care, socioeconomic status, education, or geographic location. However, numerous other studies have demonstrated that gene expression differences may also contribute to the higher mortality rates experienced by AA women, suggestive of biological differences among these two patient populations. Consequently, CRYBB2 is one gene that has consistently been associated with AA race in normal and malignant tissues. Although, its basic function in these tissues is currently unknown, higher expression of CRYBB2 is significantly correlated with poor outcome in breast, colorectal and prostate cancers in AAs. We analyzed all publically available gene expression datasets from studies focused on breast cancer health disparities and discovered that all probes detected CRYBB2 as well as its pseudogene, CRYBB2P1. It is becoming increasingly clear that pseudogenes have the ability to modify the mechanisms of their functional parental genes. However, it remains unclear whether the high expression of CRYBB2, CRYBB2P1, or both, affect cell behaviors to alter disease progression. Herein, we investigated the biological consequences of CRYBB2 and CRYBB2P1 in three basal-like TNBC cell lines (SUM159, MDA-MB-231, Hs578t) using CRISPR/Cas9 and overexpression technologies. The functional consequence of CRYBB2 and CRYBB2P1 expression were evaluated using in vitro and biochemical assays, as well as in vivo tumorigenesis studies. Our findings demonstrate overexpression of CRYBB2 and CRYBB2P1 alter cell proliferation, cytokine and growth factor production, and tumorigenesis. This data highlights the potential molecular mechanisms by which CRYBB2 and CRYBB2P1 contribute to poor patient outcome. Citation Format: Maya A. Barrow, Megan E. Martin, Denise K. Reaves, Breanna Jeffcoat, Ginger R. Smith, Michael Tarpley, Kevin P. Williams, Jodie M. Fleming. Race-associated breast cancer disparities: The role of CRYBB2 and its pseudogene [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 4058.
Abstract 10590: Characterization of Left Ventricular Regional Morphology and Function Using Cardiac Magnetic Resonance for Planning Optimal Surgical Ventricular Restoration
Authors: Srilakshmi M Adhyapak, Prahlad G Menon, V Rao Parachuri
Journal: Circulation (2013)

Background: Patient selection for surgical ventricular restoration (SVR) by accurate assessment of LV morphology & function and virtual comparison of different surgical techniques by pre-surgical p...
Abstract 2892: EGLN1 is a synthetic lethal target in <i>ARID1A</i>-mutant ovarian cancer
Authors: Kimberly J. Briggs, Chengyin Min, Hongxiang Zhang, Alan Huang
Journal: Cancer Research (2018)

Abstract The successful use of PARP inhibitors for the treatment of BRCA-mutant ovarian cancer underscores the importance of synthetic lethality as a therapeutic opportunity for tumors with loss-of-function mutations in tumor suppressor genes. Ovarian cancer ranks as the fifth deadliest cancer among women, and one ovarian cancer subtype, clear cell carcinoma, is particularly underserved. The most frequent genetic alteration in ovarian clear-cell carcinoma is loss-of-function mutation of the SWI/SNF-A complex subunit, ARID1A. We interrogated the data published by Project Achilles to determine candidate synthetic lethal partners with ARID1A in ovarian cancer, and identified EGLN1, a member of the EglN-family of prolyl hydroxylases. Inhibition of EGLN1, either genetically or pharmacologically, leads to decreased viability in ovarian cancer cell lines. Pharmacological inhibition of EGLN1 is clinically achievable as evidenced by several well-tolerated, small molecule inhibitors currently in clinical trials for the treatment of anemia in the context of chronic kidney disease. The synthetic lethal interaction of ARID1A and EGLN1 may provide a therapeutic opportunity for patients diagnosed with ovarian clear-cell carcinoma. Citation Format: Kimberly J. Briggs, Chengyin Min, Hongxiang Zhang, Alan Huang. EGLN1 is a synthetic lethal target in ARID1A-mutant 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 2892.
Hyperplastic Conotruncal Endocardial Cushions and Transposition of Great Arteries in Perlecan-Null Mice
Authors: MercedesCostell, RitaCarmona, ErikaGustafsson, MauricioGonzález-Iriarte, ReinhardFässler, RamónMuñoz-Chápuli
Journal: Circulation Research (2002)

Perlecan is a heparan-sulfate proteoglycan abundantly expressed in pericellular matrices and basement membranes during development. Inactivation of the perlecan gene in mice is lethal at two developmental stages: around E10 and around birth. We report a high incidence of malformations of the cardiac outflow tract in perlecan-deficient embryos. Complete transposition of great arteries was diagnosed in 11 out of 15 late embryos studied (73%). Three of these 11 embryos also showed malformations of semilunar valves. Mesenchymal cells in the outflow tract were abnormally abundant in mutant embryos by E9.5, when the endocardial-mesenchymal transformation starts in wild-type embryos. At E10.5, mutant embryos lacked well-defined spiral endocardial ridges, and the excess of mesenchymal cells obstructed sometimes the outflow tract lumen. Most of this anomalous mesenchyme expressed the smooth muscle cell-specific α-actin isoform, a marker of the neural crest in the outflow tract of the mouse. In wild-type embryos, p...
Differentiation Between Obesity and Insulin Resistance in the Association With C-Reactive Protein
Authors: TraceyMcLaughlin, FahimAbbasi, CindyLamendola, LynnLiang, GeraldReaven, PatriciaSchaaf, PeterReaven
Journal: Circulation (2002)

Background— Plasma C-reactive protein (CRP) concentrations are increased in obese and/or hyperinsulinemic individuals. The goal of this study was to determine if the relation between insulin resistance and CRP was independent of obesity. Methods and Results— Plasma CRP concentrations were measured before and after 3 months of calorie restriction in 38 healthy, obese women. Steady-state plasma glucose (SSPG) concentration during a 180-minute infusion of octreotide, glucose, and insulin was used to stratify participants into insulin-resistant (IR, n=20) or insulin-sensitive (n=18) groups, similar in terms of mean age (46±2 versus 44±2 years), body mass index (32.0±0.4 versus 31.4±0.3 kg/m2), and waist circumference (96±2 versus 95±2 cm). Mean CRP (0.39±0.08 versus 0.12±0.03 mg/dL, P=0.003) concentrations were higher in the IR group, as were day-long plasma glucose and insulin responses (P<0.001). There was a significant correlation at baseline between CRP and day-long plasma integrated insulin response (r=0...
Catheter Stimulation of Cardiac Parasympathetic Nerves in Humans
Authors: PatrickSchauerte, KarlMischke, JurgitaPlisiene, MatthiasWaldmann, MarkusZarse, ChristophStellbrink, ThomasSchimpf, ChristianKnackstedt, AnilSinha, PeterHanrath
Journal: Circulation (2001)

Background Cardiac parasympathetic nerves run alongside the superior vena cava (SVC) and accumulate particularly epicardially adjacent to the orifice of the coronary sinus (CS). In animals, these nerves can be electrically stimulated inside the SVC or CS, which results in negative chronotropic/dromotropic effects and negative inotropic effects in the atria but not the ventricles. Parasympathetic nerve stimulation (PS) with 20 Hz in the CS, however, also excites the atria, thereby inducing atrial fibrillation. The present study overcomes this limitation by applying high-frequency nerve stimuli within the atrial refractory period. Using this technique, we investigated for the first time whether neurophysiological effects similar to those in animals can be obtained in humans. Methods and Results In 25 patients, parasympathetic nerves were stimulated via a multipolar electrode catheter placed in the SVC (stimulation with 20 Hz; n=14) or CS (pulsed 200-Hz stimuli; n=11). A significant sinus rate decrease and p...
Abstract 13751: Categorizing the Burden of Arrhythmia in Adults With Congenital Heart Disease
Authors: David C Peritz, Vincent J Gonzalez, April Edwards, Jennifer E Nelson, Sunita J Ferns
Journal: Circulation (2015)

Introduction: Advances in surgical and medical therapies have increased the life expectancy for patients with congenital heart disease. Arrhythmias in these patients are common and multi-factorial, often due to a disruption of the hearts’ intrinsic electrical system and degenerative remodeling, secondary to varying pressure and volume loads. The aim of this study is to better characterize the association between type of structural heart disease (SHD) and clinically significant arrhythmias. Methods: We identified all adults with diagnosed congenital heart disease seen at a large tertiary care referral center between 2000 and 2014. Patients were categorized based on gender, SHD, and type of arrhythmia. We used the American Thoracic Society guidelines to group SHD into discrete categories and grouped arrhythmias as tachyarrhythmias (atrial/ventricular) and bradyarrhythmias. Results: We identified 1355 individuals with at least one congenital structural heart defect and at least one arrhythmia. Of those, the most common structural abnormality was left-sided outflow tract obstruction and the least common was congenitally corrected transposition of the great arteries. The most common category of arrhythmia identified was atrial arrhythmia and the least common was sinoatrial node dysfunction (Figure). The most common association between SHD and arrhythmia was atrial arrhythmia in patients with left-sided outflow tract obstruction. Conclusions: This study is one of the largest single-center reports linking specific structural heart defects to type of rhythm disturbance. These data may help providers better anticipate future arrhythmia development based on a patient’s underlying structural defect and offer prognostic information to patients and families. Future studies to more closely evaluate the relationship between arrhythmia patterns and specific risk factors within each category of SHD are needed.
Abstract 4381: Cordycepin promotes apoptosis in renal carcinoma cells by activating the MKK7-JNK signaling pathway through inhibition of cFLIPL expression
Authors: Ik-Soon Jang, Hyun-Jin Jang, Eunbi Jo
Journal: Cancer Research (2018)

Abstract Cellular FLICE inhibitory protein (c-FLIP) is a key anti-apoptotic regulator that associates with the signaling complex downstream of NF-κB, negatively interfering with apoptotic signaling. The role of c-FLIP downregulation by negative regulation of NF-κB signaling during apoptosis is poorly understood. Here, we demonstrate that NF-κB-mediated c-FLIPL negatively regulates the JNK signaling pathway, and that cordycepin treatment of human renal cancer cells leads to apoptosis induction through c-FLIPL inhibition. TNF-α-induced inflammatory microenvironments stimulated NF-κB signaling and the c-FLIP long form (c-FLIPL) in TK-10 cells. Specifically, cordycepin inhibited TNF-α-mediated NF-κB activation, which induced renal cancer cell apoptosis. Cordycepin downregulated GADD45B and c-FLIPL, but upregulated MKK7 and phospho-JNK, by preventing nuclear mobilization of NF-κB. Furthermore, siRNA-mediated knockdown of GADD45B in cordycepin-treated TK-10 cells considerably increased MKK7 compared to cordycepin alone. siRNA-mediated knockdown of cFLIPL prevented TNF-α-induced JNK inactivation, whereas c-FLIPL overexpression inhibited cordycepin-mediated JNK activation. The JNK inhibitor SP600125 strongly inhibited Bax expression. In nude mice, cordycepin significantly decreased tumor volume. Taken together, the results indicate that cordycepin inhibits TNF-α-mediated NF-κB/GADD45B signaling, which activates the MKK7-JNK signaling pathway through inhibition of c-FLIPL expression, thus inducing TK-10 cell apoptosis. Citation Format: Ik-Soon Jang, Hyun-Jin Jang, Eunbi Jo. Cordycepin promotes apoptosis in renal carcinoma cells by activating the MKK7-JNK signaling pathway through inhibition of cFLIPL expression [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 4381.
Abstract 15168: Interleukin-18 Enhances Mitochondrial Function in Pressure Overload through AMP-activated Protein Kinase Activation
Authors: ToshihiroIwasaku, ShinichiHirotani, AkiyoEguchi, YoshitakaOkuhara, DaisukeMorisawa, MakikoOboshi, HisashiSawada, YoshiroNaito, ToshiakiMano, TohruMasuyama
Journal: Circulation (2014)

Introduction: We have reported that serum Interleukin-18 (IL-18) concentrations increased according to worsening heart failure (HF) functional class. However, the pathological roles of serum IL-18 elevation in HF have not been fully elucidated. The purpose of this study was to elucidate the role of IL-18 in adaptation to pressure overload in IL-18 null mice. Hypothesis: We hypothesized that IL-18 plays a key role in pressure overload-induced hypertrophic responses by enhancing mitochondrial function. Methods: Ten-week-old male C57BL6/J-background wild type (WT) mice and C57BL6/J-background IL-18 null (IL-18-/-) were subjected to transaortic constriction (TAC). Cardiac function was assessed by transthoracic echocardiography every week. Two weeks after TAC, myocardial samples were obtained. Detection of cardiac gene expressions by q-RT PCR and quantification of phospho-proteins by western blot were performed. An AMPK activator (AICAR 100mg/kg,) was given intraperitoneally everyday after TAC procedure. Resul...
Abstract 1147: Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy
Authors: Peh Yean Cheah, Yee Syuen Low, Michelle Lo, See Aik Tang, Alphaeus Ng, Choong Leong Tang, Siew Heng Wong
Journal: Cancer Research (2018)

Abstract Colorectal Cancer (CRC) is the third leading cause of cancer death worldwide. Majority of mortality is attributable to metastasis to distal organs. Current treatment targeting the ERK/MAPK pathway used monoclonal anti-EGFR antibody after the first line of chemotherapy fails. However these treatments are only effective for a small percentage of patients with wild-type KRAS, and these same patients eventually develop resistance. Small molecule drugs are toxic and have limited success. A combination of antibodies is an attractive alternative. This study aims to investigate whether anti-KRAS antibody can enter live cells in an individualized ex vivo culture system and whether it can bind and inactivate KRAS. The transient culture has advantages over cell line study as it better mimics the human colonic environment and tumors can be compared to their matched normals to partially address the problem of heterogeneity. Samples were obtained from patients' resected tumour and matched mucosa, cultured ex vivo, and immunostaining performed. We show that anti-KRAS antibody is internalized in both the cultured mucosa and tumor crypt cells prior to fixation. Subcellular localization of the internalized antibody in the mucosa cells is similar in the pre-fixed and post-fixed cells. In contrast, the internal cell membrane staining observed in post-fixed tumor cells appear more cytoplasmic and 'punctated' in the pre-fixed tumors, mimicking that of the mucosa cells suggesting that the internalized anti-KRAS may have altered the sub-cellular localization and hence cycling of KRAS. Furthermore, staining with anti-keratin antibody indicates that live tumor cells treated with anti-KRAS has partial reversal of the phenotype to become more like the regular striated pattern of the matched mucosa. Preliminary double labelling of cultured tumours with monoclonal anti-KRAS prior to fixation and polyclonal anti-KRAS post-fixation revealed punctate staining of KRAS in the cytoplasm that were mainly non-overlapping suggesting that the punctate structures are in different compartments. Citation Format: Peh Yean Cheah, Yee Syuen Low, Michelle Lo, See Aik Tang, Alphaeus Ng, Choong Leong Tang, Siew Heng Wong. Developing an individualized human colonic crypt cell culture as an ex vivo model for immunotherapy [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 1147.
Projections in Breast and Lung Cancer Mortality among Women: A Bayesian Analysis of 52 Countries Worldwide
Authors: Juan Carlos Martín-Sánchez, Nuno Lunet, Adrián González-Marrón, Cristina Lidón-Moyano, Nuria Matilla-Santander, Ramon Clèries, Matteo Malvezzi, Eva Negri, Samantha Morais, Ana Rute Costa, Ana Ferro, Luisa Lopes-Conceição, Carlo La Vecchia, Jose M. Martínez-Sánchez
Journal: Cancer Research (2018)

Abstract Among women, lung cancer mortality rates have surpassed those for breast cancer in several countries. This reflects the breast cancer mortality declines due to access to screening and effective treatment alongside the entrance of certain countries in stages of the tobacco epidemic in which smoking becomes more prevalent in women. In this study, we project lung and breast cancer mortality until 2030 in 52 countries. Cancer mortality data were obtained from the WHO Mortality Database. Age-standardized mortality rates (ASMR), per 100,000, were calculated (direct method) for 2008 to 2014 and projected for the years 2015, 2020, 2025, and 2030 using a Bayesian log-linear Poisson model. In 52 countries studied around the world, between 2015 and 2030, the median ASMR are projected to increase for lung cancer, from 11.2 to 16.0, whereas declines are expected for breast cancer, from 16.1 to 14.7. In the same period, the ASMR will decrease in 36 countries for breast cancer and in 15 countries for lung cancer. In half of the countries analyzed, and in nearly three quarters of those classified as high-income countries, the ASMR for lung cancer has already surpassed or will surpass the breast cancer ASMR before 2030. The mortality for lung and breast cancer is higher in high-income countries than in middle-income countries; lung cancer mortality is lower in the latter because the tobacco epidemic is not yet widespread. Due to these observed characteristics of lung cancer, primary prevention should still be a key factor to decrease lung cancer mortality. Significance: The mortality for lung and breast cancer is projected to be higher in high-income countries than in middle-income countries, where lung cancer mortality is expected to surpass breast cancer mortality before 2030. Cancer Res; 78(15); 4436–42. ©2018 AACR.