tbuckley/cabot-search huggingface dataset:
Abstract 4999: Identifying intercellular phenotypic stability factors for a hybrid epithelial-mesenchymal phenotype
Authors: Mohit Kumar Jolly, Federico Bocci, Satyendra C. Tripathi, Mitzi Aguilar, Samir M. Hanash, Herbert Levine, Jose N. Onuchic
Journal: Cancer Research (2018)

Abstract Epithelial-mesenchymal transition (EMT) and its reverse Mesenchymal-epithelial transition (MET) are crucial for embryonic development, wound healing and cancer metastasis. Cells need not undergo full EMT or MET, rather they can maintain stably a hybrid epithelial/mesenchymal (E/M) phenotype and thus exhibit collective cell migration, forming clusters of circulating tumor cells - the primary drivers of metastasis. Mechanisms enabling cells to exhibit a hybrid E/M phenotype stably remain elusive. Here, using an integrated experimental-computational approach, we identify ‘phenotypic stability factors' (PSFs) that can stabilize a hybrid E/M phenotype by mediating cell-cell communication through Notch signaling pathway. Our mathematical model predicts that Numb or Numb-like (Numbl) can inhibit a full EMT and stabilize a hybrid E/M phenotype. This prediction is validated by the observation that knockdown of Numb in stably hybrid E/M cells H1975 results in a full EMT, thereby indicating that Numb behaves as a PSF. Generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumor-initiation ability. Our model also suggests another PSF – Nrf2 (nuclear factor E2-related factor 2) – that couples both to EMT and Notch signaling, and stabilizes a hybrid E/M phenotype too. Intriguingly, Nrf2 levels are maximally observed in a hybrid E/M phenotype as compared to purely epithelial or mesenchymal phenotypes. Finally, high levels of Numb or Nrf2 also correlate with a worse survival in multiple independent cancer datasets, strengthening the association of a hybrid E/M phenotype with increased cancer aggressiveness. Citation Format: Mohit Kumar Jolly, Federico Bocci, Satyendra C. Tripathi, Mitzi Aguilar, Samir M. Hanash, Herbert Levine, Jose N. Onuchic. Identifying intercellular phenotypic stability factors for a hybrid epithelial-mesenchymal phenotype [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 4999.
Burden of Urological Complications in Men and Women With Long-standing Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Cohort
Authors: Hunter Wessells, Barbara H. Braffett, Sarah K. Holt, Alan M. Jacobson, John W. Kusek, Catherine Cowie, Rodney L. Dunn, Aruna V. Sarma
Journal: Diabetes Care (2018)

Type 1 diabetes has been associated with high rates of urinary and sexual problems, but the cumulative burden and overlap of these complications are unknown. We sought to determine prevalence of urological complications in persons with type 1 diabetes, associations with clinical and diabetes-related factors, and rates of emergence, persistence, and remission.This ancillary longitudinal study among participants in the Diabetes Control and Complications Trial (DCCT) and observational follow-up study Epidemiology of Diabetes Interventions and Complications (EDIC) (652 women and 713 men) was conducted in 2003 and 2010/2011. Urinary incontinence (UI), lower urinary tract symptoms, urinary tract infection, female sexual dysfunction, erectile dysfunction, low male sexual desire, and orgasmic dysfunction were measured with validated instruments. Logistic regression determined association of complications with demographics and clinical characteristics.Of sexually active women completing the 2010/2011 survey, 35% reported no complications, 39% had one, 19% two, 5% three, and 2% four. In men, 31% had no complications, 36% had one, 22% two, 9% three, and 3% four. Sexual dysfunction was most prevalent (42% women and 45% men) followed by UI in women (31%) and low sexual desire in men (40%). Urological complications were associated with age, BMI, and HbA1c. Remission rates ranged from 4 to 12% over the 7-year interval between surveys.Urological complications are prevalent and frequently co-occur in persons with type 1 diabetes. Remission rates in a minority subset indicate a rationale for future studies to mitigate the onset or impact of urological complications of diabetes.
Prognosis of early breast cancer patients treated with sentinel node biopsy: A prospective study from the Japanese society for sentinel node navigation surgery.
Authors: Shigeru Imoto, Takashi Aikou, Hiroyuki Takei, Noriaki Wada, Tomohiko Aihara, Masaaki Inaba, Kazuyoshi Motomura, Norikazu Masuda, Takeshi Nagashima, Hiromitsu Jinno, Daishu Miura, Mari Saito, Satoshi Morita, Junichi Sakamoto, Masaki Kitajima
Journal: Journal of Clinical Oncology (2012)

1106 Background: Sentinel node biopsy (SNB) is a new standard of care for clinically node-negative breast cancer patients. Our society conducted a prospective study on SNB for early breast cancer patients from Jul 2004 to Oct 2005 (UMIN000006126). A preliminary result regarding with success rates of multiple mapping methods and the adverse events was presented at the 2007 ASCO. We observed patient’s outcome for 5 years. Methods: Of the 1,411 cases registered, the objects were 1,107 cases excluding cases with bilateral breast cancer, non-invasive breast cancer, past history of other malignancy or failure of SNB and cases treated with primary chemotherapy or endocrine therapy. Adjuvant therapy and breast irradiation were decided by physician’s discretion and patient’s preference. To evaluate the risk of isolated tumor cells or micrometastases in sentinel lymph nodes (SLN), clinicopathological factors were analyzed using the Cox regression model. Results: After a median follow-up of 62 months, there were 85 recurrences and 14 deaths. 5-year Kaplan-Meire estimates for disease-free survival and overall survival (OS) were 92.6% and 97.5% in 848 cases with pN0(sn), 96.2% and 100% in 26 with pN0(i+)(sn), 89.3% and 95.3% in 68 with pN1mi(sn) and 82.8% and 92.0% in 165 with pN1(sn) or greater nodal metastases. No axillary lymph node dissection (ALND) was performed in 809 cases (95.4%), 18 (69.2%), 38 (55.9%), and 24 (14.5%), respectively. Regional node recurrence was found in 8 cases (0.9%), 0 (0%), 2 (2.9%) and 2 (1.2%), respectively. Univariate analysis showed that pN1(sn) or greater nodal metastases, pT2-4, nuclear grade 3, lymphovascular invasion, negative hormone receptor status, SNB followed by ALND, chemotherapy therapy were significant risk factors for OS. However, from multivariate analysis, nuclear grade 3, lymphovascular invasion and SNB followed by ALND were independent unfavorable prognostic factors (hazard ratio: 3.21, 2.61 and 3.93). Conclusions: Although a non-randomized prospective study, isolated tumor cells and micrometastases in SLN did not affect patient’s survival. ALND should be omitted for early breast patients with those metastases.
Abstract 16233: Sex Differences in Mortality After Myocardial Infarction: The Role of Post Pci Flow and its Relation to Time Delay to Reperfusion
Authors: Edina Cenko, Beatrice Ricci, Sasko Kedev, Zorana Vasiljevic, Oliver Kalpak, Davor Milicic, Boidarka Kneevic, Maria Dorobantu, Olivia Manfrini, Lina Badimon, Raffaele Bugiardini
Journal: Circulation (2016)

Introduction: Little is known regarding gender differences in coronary flow and 30 day mortality after primary PCI in STEMI, despite blood flow is a major determinant of patients’ prognosis. Hypoth...
MinK-Related Peptide 1 Associates With Kv4.2 and Modulates Its Gating Function
Authors: MeiZhang, MinJiang, Gea-NyTseng
Journal: Circulation Research (2001)

Abstract—Inherited mutations and a polymorphism in minK-related peptide 1 (MiRP1) have been linked to congenital or acquired long-QT syndrome, pointing to the importance of MiRP1 in maintaining the cardiac electrical stability. We tested whether MiRP1 could affect the function of Kv4.x (x=2 and 3), the major pore-forming (α) subunits of transient outward (Ito) channels in the heart. We used the Xenopus oocyte expression system to examine the effects of MiRP1 on Kv4.x channel gating kinetics and current amplitude and correlated these effects with MiRP1 expression level. MiRP1 slowed the rates of Kv4.2 activation and inactivation and shifted the voltage dependence of channel gating in the positive direction. These effects had a similar “dose” dependence: they plateaued at a cRNA ratio (MiRP1:Kv4.2) of 13:1, with half-maximum effects at estimated cRNA ratios of 2 to 4. On the other hand, MiRP1 had no significant effects on Kv4.2 current amplitude in the same range of expression level. When expressed at a com...
Abstract 2324: Docosahexaenoic acid-induced Nrf2 may be correlated with cell death by amplification of oxidative stress via induction of klf9 in cervical cancer cells
Authors: Kaipeng Jing, Soyeon Shin, Seung-Hyeon Han, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim
Journal: Cancer Research (2018)

Abstract NF-E2-related transcription factor-2 (Nrf2) is a key transcriptional factor regulating antioxidant gene expression and protection from oxidant damage. Docosahexaenoic acid (DHA) as one of ω3-polyunsaturated fatty acids has anticancer action through several mechanisms. Here we report that DHA-induced Nrf2 is related to cell death, not survival in HeLa cell. We confirmed DHA-induced apoptotic cell death using PARP cleavage, Anexin V staing, and TUNEL positive staining assay. DHA-triggering ROS production increased the level Nrf2 and decreased keap1 in dose- and time-dependent manner. Increased Nrf2 by DHA was partially Keap1 dependent. DHA activated Nrf2 signaling by increasing its translation and the Nrf2 was translocated from cytosol to nucleus. Upregulation of DHA-mediated Nrf2 was also confirmed by increase of heme oxygenase-1 (HO-1) expression. DHA-induced Nrf2 increased the level of Kruppel-like factor 9 (klf9) and then decreased thioredoxin reductase 2 (Txnrd2) in dose- and time-dependent manner. These results suggest that DHA-induced ROS increases Nrf2 and the Nrf2 is related to cell death by increase of klf9 and decrease of Txnrd2 in HeLa cells. Thus, utilization of ω3-PUFAs may represent a promising therapeutic approach for chemoprevention and treatment of human cervical cancer [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)] Citation Format: Kaipeng Jing, Soyeon Shin, Seung-Hyeon Han, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Docosahexaenoic acid-induced Nrf2 may be correlated with cell death by amplification of oxidative stress via induction of klf9 in cervical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2324.
Abstract #5087: The ratio of IFN-gamma/IL-10 productions is a useful prognostic indicator and it was improved by mushroom extract in patients with malignant diseases
Authors: Ariaki Nagayama, Takashi Kawanishi, Yasunori Matsui, Makoto Tamesada, Masahiko Shibata
Journal: Cancer Research (2009)

Host-immune functions of patients with cancer have been reported to be suppressed by Th1/Th2 imbalance that is regulated by cytokines such as IFN-\#947; and IL-10. Mushroom extracts have been proven to improve host-immune functions in cancer patients, and have been developed to be used as Biological Response Modifiers. We have evaluated the usefulness of total cytokine production by peripheral blood as a prognostic indicator compared with Th1 (CD4+IFN-\#947;+ cells) / Th2 (CD4+IL-4+ cells) balance by general flow cytometry analysis. We also studied 5 kinds of mushroom extracts that have been widely used in Asia in their immunomodulatory effects in cancer patients. Thirteen patients with variable malignant diseases including prostatic, colon, kidney, gastric and lung cancer and 13 patients who have received surgery but not recurred (cancer free: CF) were entered in this study. Lentinula edodes mycelia, Cordyceps sinensis mycelia, Phellinus linteus, Ganoderma lucidum and Agaricus blazei were measured in IFN-\#947; production by peripheral blood of each patient and the one that responded mostly was selected. It was administered to each patient for 20 weeks. The values of IFN-\#947; and IL-10 were measured by ELISA at 2 points, before and 20 weeks after the administration. Although the ratios of IFN-\#947;/IL-10 productions in patients with poor prognosis who died within 6 months did not increase after treatment, those with good prognosis statistically increased (from 0.58±0.71 to 2.97±6.46, p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5087.
Abstract 2732: Cell-based reporter bioassays to evaluate the Fc gamma receptor-dependent agonistic activities for therapeutic antibodies targeting immune costimulatory receptors
Authors: Jun Wang, Michael Beck, Jamison Grailer, Pete Stecha, Jim Hartnett, Frank Fan, Mei Cong, Zhi-Jie Jey Cheng
Journal: Cancer Research (2018)

Abstract Immune costimulatory receptors synergize with TCR-CD3 signaling to promote cell cycle progression, cytokine production, T cell survival and effector functions. They belong to immunoglobulin super-family (CD28, ICOS) and tumor necrosis factor receptor (TNFR) superfamily (4-1BB, OX40, CD27, CD40, GITR, DR3, and HVEM). Preclinical and clinical evidence shows that agonist antibodies against costimulatory receptors can stimulate antitumor immunity and are emerging as a promising approach for cancer immunotherapies. Furthermore, FcγR engagement, especially FcγRIIB due to its bioavailability, has been shown to provide a crosslinking scaffold for the antibody IgG to facilitate TNFR clustering/activation and become requisites for some agonist antibody activities. Here, we report the development of a suite of cell-based reporter bioassays to quantitatively measure the potencies of therapeutic antibodies designed to target costimulatory receptors. For this, we developed engineered effector cells that express each costimulatory receptor and a luciferase reporter driven by response element that specifically responds to costimulatory receptor signaling. We also developed a FcγR-expressing cell line to evaluate the involvement of FcγR in agonist antibody-mediated costimulatory signaling. The assays are specific for each costimulatory receptor, and can be used to detect both agonistic and blocking activities for the antibodies. When co-incubated with the engineered FcγR-expressing cells, they are able to show the Fcγ receptor-dependent or independent agonist activities. In summary, these reporter bioassays can serve as powerful tools in immunotherapy drug development for antibody screening and potency determination. Citation Format: Jun Wang, Michael Beck, Jamison Grailer, Pete Stecha, Jim Hartnett, Frank Fan, Mei Cong, Zhi-Jie Jey Cheng. Cell-based reporter bioassays to evaluate the Fc gamma receptor-dependent agonistic activities for therapeutic antibodies targeting immune costimulatory receptors [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 2732.
Long-Term Effects of Enzyme Replacement Therapy on Fabry Cardiomyopathy
Authors: FrankWeidemann, MarkusNiemann, FrankBreunig, SebastianHerrmann, MeinradBeer, StefanStörk, WolframVoelker, GeorgErtl, ChristophWanner, JörgStrotmann
Journal: Circulation (2009)

Background— Enzyme replacement therapy with recombinant α-galactosidase A reduces left ventricular hypertrophy and improves regional myocardial function in patients with Fabry disease during short-term treatment. Whether enzyme replacement therapy is effective in all stages of Fabry cardiomyopathy during long-term follow-up is unknown. Methods and Results— We studied 32 Fabry patients over a period of 3 years regarding disease progression and clinical outcome under enzyme replacement therapy. Regional myocardial fibrosis was assessed by magnetic resonance imaging late-enhancement technique. Echocardiographic myocardial mass was calculated with the Devereux formula, and myocardial function was quantified by ultrasonic strain-rate imaging. In addition, exercise capacity was measured by bicycle stress test. All measurements were repeated at yearly intervals. At baseline, 9 patients demonstrated at least 2 fibrotic left ventricular segments (severe myocardial fibrosis), 11 had 1 left ventricular segment affec...
Abstract 18712: Adeno-associated Viral Gene Delivery of Calsequestrin 2 Protects Adult Calsequestrin 2-R33Q Knock-in Mice From Developing Ventricular Tachycardias
Authors: Marco Denegri, José E Avelino-Cruz, Veronica C De Giusti, Francesco Lodola, Antonio Curcio, Rossana Bongianino, Valentina Leccioli, Simona Boncompagni, Feliciano Protasi, Alberto Auricchio, Carlo Napolitano, Silvia G Priori
Journal: Circulation (2012)

Background. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal recessive arrhythmogenic disease associated with mutations in the calsequestrin 2 ( CASQ2 ) gene. We previously demonstrated that CASQ2 gene delivery was able to rescue the arrhythmic phenotype in CASQ2 knock-out (KO) mice 5 months after the viral infection. The aim of the present study is to investigate the long-term effects of viral gene delivery in CASQ2-R33Q missense mutation mouse model. Methods. Newborn CPVT mice were infected with adeno-associated viral vector 9 (AAV9) containing the coding sequence of the wild type CASQ2 co-expressed with green fluorescent protein (GFP) gene. Furthermore, we evaluated the effect at 7 and 12 months after viral infection by in vivo ECG analysis, in vitro electrophysiological and molecular assays. Results. Telemeter recording of ECG demonstrated in vivo ventricular tachycardias (VT) after epinephrine (2 mg/Kg) administration in only 17% (2 out of 12) of the infected mice, while 87% (7/8) of the control CASQ2-R33Q homozygous mice presented a clear arrhythmic phenotype (p&lt;0.005). Additionally, electrophysiological analysis showed that delayed after depolarization (DADs) and triggered activity (TA) were almost abolished in GFP-positive cardiomyocytes (7 months: DADs: 0%, TA 0%, n=18; 12 months: DADs: 8%, TA: 8%, n=12) in comparison with their internal control (GFP-negative cells, 7 months: DADs:100%, TA: 83%, n=6; 12 months: DADs: 100%, TA: 71%, n=7; p&lt;0.001). Finally, western blot revealed increased CASQ2 expression in the infected mice and immunofluorescence assay indicated its correct localization along the z-lines. Conclusions. In the present work we show that the viral expression of CASQ2 is effective for a long period of time and is able to revert the functional abnormalities of the mutant endogenous protein and to prevent life-threatening arrhythmias in the knock-in CASQ2-R33Q mice. These data suggest that despite R33Q mice, at variance with KO mice, express abnormal CASQ2, the gene replacement therapy is still able to prevent arrhythmogenic mechanisms in vitro and VTs in vivo thus suggesting that CASQ2-gene transfer may become a novel therapy for recessive CPVT.
Contractile Properties of the Cultured Vascular Smooth Muscle Cells
Authors: DanBi, JunjiNishimura, NaohisaNiiro, KatsuyaHirano, HideoKanaide
Journal: Circulation Research (2005)

Vascular smooth muscle cells (VSMCs) have a remarkable degree of plasticity and in response to vascular injury, they can change to a dedifferentiated state that can be typically seen in cell cultures. Recently, Y27632, a Rho kinase inhibitor, has been reported to preferentially correct hypertension in a hypertensive rat model. We thus tested the hypothesis that the contraction of the cultured VSMCs might be more dependent on the function of RhoA than the VSMCs in fresh tissue. For this purpose, a tissue-like ring preparation was made using the cultured porcine coronary artery SMCs (CASMCs) and collagen gel (reconstituted ring: R-ring). The R-ring developed an isometric tension on stimulation by high external K+ or various receptor agonists. The phorbol ester (a protein kinase C (PKC) activator)-induced contraction of the intact R-ring was greatly inhibited, while the GTPγS (an activator of RhoA)-induced and Ca2+-independent contraction of permeabilized R-ring was greatly enhanced, in comparison to the fre...
Abstract 386: Identification of Genetic Regulatory Networks for Insulin Resistance in Multiple Populations of Diverse Ethnicities
Authors: Le Shu, Yuqi Zhao, Aldons J Lusis, Ke Hao, Thomas Quertermous, Joshua W Knowles, Xia Yang
Journal: Circulation Research (2017)

Insulin resistance (IR) is a critical pathogenic factor for highly prevalent modern cardiometabolic diseases, including coronary artery disease (CAD) and type 2 diabetes (T2D). However, the molecular circuitries underlying IR remain to be elucidated. The GENEticS of Insulin Sensitivity Consortium (GENESIS) conducted genome-wide association studies (GWAS) for direct measures of IR using euglycemic clamp or insulin suppression test. We sought to identify gene networks and their key intervening drivers for IR by performing a comprehensive integrative analysis leveraging GWAS data from seven GENESIS cohorts representing three ethnic groups - Europeans, Asians and Hispanics, along with expression quantitative trait loci, ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from IR relevant tissues. Integration of the multi-ethnic GWAS with diverse functional genomics information captured shared IR pathways and networks across ethnicities that are independent of body mass index, including GLUT4 translocation regulation, insulin signaling, MAPK signaling, interleukin signaling, extracellular matrix, branched-chain amino acids metabolisms, cell cycle, and oxidative phosphorylation. Further integration of these GWAS-informed IR processes with graphical gene networks uncovered potential key regulators including HADH, COX5A, VCAN and TOP2A , whose network neighbors are consistently enriched for the genetic association signals of IR across ethnicities, and show significant correlation with IR, fasting glucose and insulin levels in the transcriptomic-wide association data from a Hybrid Mouse Diversity Panel comprised of &gt;100 strains fed with high-fat diet. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide new understanding of the pathways, gene networks and potential regulators contributing to IR. These results will also facilitate future functional investigations to unveil how DNA variations translate into IR.