tbuckley/cabot-search huggingface dataset:
Abstract 4359: Several cancer types are associated with increased expression and activity of the ECT2 RhoGEF and decreased expression and activity of the DLC1 RhoGAP, leading to increased RhoA activity
Authors: Dunrui Wang, Xiaolan Qian, Marian E. Durkin, Alexander G. Papageorge, Douglas R. Lowy
Journal: Cancer Research (2018)

Abstract RhoA, which is a member of the Ras family of small GTPases, whose proteins cycle between an active GTP-bound form and an inactive GDP-bound form, frequently has high activity in advanced cancer. The RhoA protein is activated by RhoGEFs, which catalyze replacement of bound-GDP with bound-GTP, and inactivated by RhoGAPs, which hydrolyze bound-GTP to bound-GDP. In this study, we have used the The Cancer Genome Atlas (TCGA) and the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to examine the relationship between a specific RhoGEF, ECT2, and a specific RhoGAP, DLC1, and experimentally tested the biological relevance of some key findings. Using the TCGA dabase, we have found increased expression of the ECT2 RhoGEF frequently occurs in synchrony with decreased expression of the DLC1 RhoGAP in several tumor types, including lung adenocarcinoma, lung squamous cell carcinoma, and hepatocellular cancer. In lung adenocarcinoma, the combination of high ECT2 expression and low DLC1 expression level is more common in poorly differentiated tumors than in well differentiated ones. Using other publicly available datasets from NCBI Gene Expression Omnibus (GEO), the expression DLC1 and ECT2 was found to be cell cycle related, with higher DLC1 being observed exclusively in the G0 phase, while ECT2 was higher during the cell cycle, relative to G0, and peaked in the G2/M phase. In CPTAC, phosphorylation of a specific ECT2 amino acid (S861) is correlated with a poor prognosis in breast cancer. Consistent with this observation, experimental mutation of ECT2 S861 to A861 results in an ECT2 gene with loss-of-function. Point mutation of ECT2 and DLC1 were found at overall frequencies of 1.7% and 4.7%, respectively, in the tumors of the TCGA database. These cancer-associated mutations occur along the entire length of the ECT2 and DLC1 proteins, rather than being located primarily in the Rho-GEF domain of ECT2 or the Rho-GAP domain of DLC1, and experimental analysis of a subset of these mutants indicates that most of the ECT2 mutants are gain-of-function, while most of the DLC1 mutants are loss-of-function. Our results imply that ECT2 and DLC1 frequently act in concert, but in opposite directions, in cancer to increase RhoA activity. * Authors contributed equally to this abstract Citation Format: Dunrui Wang, Xiaolan Qian, Marian E. Durkin, Alexander G. Papageorge, Douglas R. Lowy. Several cancer types are associated with increased expression and activity of the ECT2 RhoGEF and decreased expression and activity of the DLC1 RhoGAP, leading to increased RhoA 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 4359.
Intestinal Metaproteomics Reveals Host-Microbiota Interactions in Subjects at Risk for Type 1 Diabetes
Authors: Patrick G. Gavin, Jane A. Mullaney, Dorothy Loo, Kim-Anh Lê Cao, Peter A. Gottlieb, Michelle M. Hill, Danny Zipris, Emma E. Hamilton-Williams
Journal: Diabetes Care (2018)

OBJECTIVE Dysbiosis of the gut microbiota has been linked to disease pathogenesis in type 1 diabetes, yet the functional consequences to the host of this dysbiosis are unknown. We investigated the functional interactions between the microbiota and the host associated with type 1 diabetes disease risk. RESEARCH DESIGN AND METHODS We performed a cross-sectional analysis of stool samples from subjects with recent-onset type 1 diabetes (n = 33), islet autoantibody–positive subjects (n = 17), low-risk autoantibody-negative subjects (n = 29), and healthy subjects (n = 22). Metaproteomic analysis was used to identify gut- and pancreas-derived host and microbial proteins, and these data were integrated with sequencing-based microbiota profiling. RESULTS Both human (host-derived) proteins and microbial-derived proteins could be used to differentiate new-onset and islet autoantibody–positive subjects from low-risk subjects. Significant alterations were identified in the prevalence of host proteins associated with exocrine pancreas output, inflammation, and mucosal function. Integrative analysis showed that microbial taxa associated with host proteins involved in maintaining function of the mucous barrier, microvilli adhesion, and exocrine pancreas were depleted in patients with new-onset type 1 diabetes. CONCLUSIONS These data support that patients with type 1 diabetes have increased intestinal inflammation and decreased barrier function. They also confirmed that pancreatic exocrine dysfunction occurs in new-onset type 1 diabetes and show for the first time that this dysfunction is present in high-risk individuals before disease onset. The data identify a unique type 1 diabetes–associated signature in stool that may be useful as a means to monitor disease progression or response to therapies aimed at restoring a healthy microbiota.
Abstract 464: Cell death and senescence: Role of protein kinase C in promoting senescence
Authors: Etta Livneh, Assaf Ben Ari, Udi Zurgil
Journal: Cancer Research (2018)

Abstract Senescence is characterized by permanent cell cycle arrest and loss of proliferative capacity, despite continued viability and metabolic activity. Senescent cells undergo massive genome modulation including induction of the senescence-associated secretory phenotype (SAPS). Components of SASP can implement cell cycle arrest or recruit the immune system to clear senescent cells, thus contributing to tumor suppression. However, some secreted pro-inflammation molecules, act as pro-tumorigenic agents contributing to tumor progression, suggesting that elimination of senescent cells could be beneficial. Very few studies showed a role for PKC in senescence. Here we show that PKCeta, an epithelial specific and anti-apoptotic kinase (epithelia is the origin of about 90% of human tumors), promotes senescence induced by oxidative stress and DNA damage. Using PKCeta-knockdown breast adenocarcinoma MCF-7 cells we show that PKCeta promotes senescence induced by oxidative stress and DNA damage via its ability to upregulate the expression of the cell cycle inhibitors p21Cip1 and p27Kip1 and to modulate transcription of major components of SASP such as IL-6 and IL-8. Moreover, we demonstrate that PKCeta creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor. Thus, the expression of PKCeta modulates major components of SASP. Furthermore, our studies demonstrate that PKCeta interferes with γH2AX phosphorylation, which mark DNA double-strand breaks for repair. The phosphorylation of γH2AX may reflect the extent of DNA breaks but also the cellular response to DNA damage. Our experiments suggest that the response to DNA damage (repair processes) was more efficient in PKCeta-knockdown cells. The phosphorylation on ATM and Chk2 was also lower in PKCeta expressing cells. Revealing the molecular regulators of senescence will improve our ability to develop new therapeutic strategies for clearing tumor cells. Our studies showing a role for PKCeta in senescence could identify PKCeta and/or its activated signaling cascades as targets for intervention senescence induction. Since PKCeta is highly expressed in epithelia that are the origin of about 90% of human tumors, this may provide critical inhibitors as therapeutic adjuvants for different types of carcinomas. Citation Format: Etta Livneh, Assaf Ben Ari, Udi Zurgil. Cell death and senescence: Role of protein kinase C in promoting senescence [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 464.
Abstract 3869: A nanofiber-based biosensor for ultrasensitive detection of serum CRP in melanoma
Authors: Zuan-Tao Lin, Yaxi Li, Tianfu Wu
Journal: Cancer Research (2018)

Abstract Purpose: Early detection of melanoma is important to improve survival; however, the technology for accurate early diagnosis is still challenging. This study is to develop a novel polymeric biosensor that could provide superior sensitivity in the detection of potential early biomarkers (e.g., CRP) of melanoma. Experimental Procedure: Our strategy is to construct a highly specific molecular recognition core and a highly responsive transducer made of conductive polypyrrole (PPy) nanofibers. Briefly, a polymeric matrix was produced by polymerization of acrylamide (AM), methylenebisacrylamide (MBAA), N-Isopropylacrylamide (NIPAAm) and CRP/CRP-aptamer complex first. Next, taking advantage of the porous structure of this NIPAAm-AM-CRP-aptamer/CRP polymeric matrix, we synthesized a polypyrrole-based conductive nanofiber structure using copper phthalocyanine-3,4',4'',4‴-tetrasulfonic acid tetrasodium salt (CuPT) as a dopant counterion in situ to achieve uniformly dispersed nanofibers within the polymeric network of NIPAAm-AM-CRP-aptamer/CRP. After removing CRP recombinant protein, we were able to obtain a robust CuPT-PPy/NIPAAm-AM polymeric sensor for the detection of CRP with high sensitivity and selectivity. Two-step signal amplification cascades were involved in this CRP-specific polymeric sensor: 1) CRP binding-induced polymeric network shrinkage; 2) shrinkage-triggered conductance change of the polymeric network. Therefore, serum CRP levels could be quantitatively analyzed through monitoring the conductance change caused by polymeric network shrinkage upon aptamer-CRP binding. Results: The limit of detection (LOD) of the polymeric sensor for detection of human recombinant CRP could reach 10^−19 M. The Fourier transform infrared (FT-IR) spectra confirmed the chemical structure of the polymeric network, and the morphology was observed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). The results of FT-IR reveal that CuPT-PPy nanofiber was successfully synthesized in situ. The nanostructure of the nanofibers was clearly observed using SEM and AFM, indicating that the diameter of nanofiber is about 20 nm. This CRP-specific biosensor and a commercial CRP ELISA kit were used to perform side-by-side measurement of serum CRP in melanoma patients. Conclusion: Our results indicated that this CRP-specific conductive polymeric senor is highly sensitive and selective in accurately discriminating melanoma patients from healthy controls. Such a flexible conductive polymeric biosensor may hold great promise as a point-of-care device in the diagnostics of melanoma or other cancers. Citation Format: Zuan-Tao Lin, Yaxi Li, Tianfu Wu. A nanofiber-based biosensor for ultrasensitive detection of serum CRP in melanoma [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 3869.
Abstract 17427: Cessation of Continuous Flow LVAD-induced Gastrointestinal Bleeding After Heart Transplantation
Authors: Kyung Taek Oh, Omar Saeed, Daniel Goldstein, Snehal R Patel, Ulrich P Jorde
Journal: Circulation (2016)

Objective: It is well established that continuous flow left ventricular assist device (CF LVAD) therapy induces gastrointestinal bleeding (GIB). What has been widely presumed but not documented to ...
Abstract 5493: Targeted inhibition of glutaminase in GRM1-expressing melanoma cells inhibits cell proliferation by reducing glutamate bioavailability
Authors: Raj Shah, Mengying Zhu, Andrew Boreland, Fabian Filipp, Suzie Chen
Journal: Cancer Research (2018)

Abstract Aberrant glutamatergic signaling has been implicated in many cancer types. Our laboratory has previously illustrated the role of metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1 is also the predominant excitatory neurotransmitter in the central nervous system. We have demonstrated significant upregulation of glutaminase (GLS) expression in GRM1 expressing melanoma cells, resulting in excess glutamate production and the establishment of autocrine loops in vitro. GLS catalyzes the first step in glutamine metabolism–the conversion of glutamine to glutamate. Comparison of glutamate levels in circulating blood plasma between melanoma prone and wild type mice showed elevated glutamate levels in melanoma prone GRM1-transgenic mice, suggesting that aberrant GRM1 expression also promotes an increase in circulating glutamate, to ensure constitutive activation of the GRM1 receptor and its downstream signaling affecters in vivo. Inclusion of CB-839, a potent, selective, and orally bioavailable inhibitor of GLS, resulted in significant inhibition of GRM1+ melanoma cell proliferation compared to GRM1- ones. We also demonstrated that treatment with Riluzole, an inhibitor of glutamatergic signaling by decreasing the available ligand, glutamate, led to significantly reduced melanoma cell proliferation in vitro and tumor progression in vivo. We found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1+ melanoma cells led to synergistic suppression of cell proliferation in vitro. Furthermore, we found that CB-839 altered the function not the expression of GLS in melanoma cells. Additionally, we also discovered that manipulation of GRM1 expression by genetic means led to robust parallel changes in gene expression levels and intracellular glutamate concentrations by mass spectrometry analysis, as well as the endogenous levels of GLS in melanoma cells, suggesting association between GRM1 and GLS. The sensitivity of GRM1+ melanoma cells to modulation of GLS point to the dependency of these cells to glutamate amounts via GLS activity. We are continuing to investigate the mechanisms and regulation of GLS in our experimental system, with the goal of developing a rational approach for the treatment of GRM1 expressing tumors. Citation Format: Raj Shah, Mengying Zhu, Andrew Boreland, Fabian Filipp, Suzie Chen. Targeted inhibition of glutaminase in GRM1-expressing melanoma cells inhibits cell proliferation by reducing glutamate bioavailability [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 5493.
Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone
Authors: Chang-XiBai, JunkoKurokawa, MasajiTamagawa, HaruakiNakaya, TetsushiFurukawa
Journal: Circulation (2005)

Background— Women have longer QTc intervals than men and are at greater risk for arrhythmias associated with long QTc intervals, such as drug-induced torsade de pointes. Recent clinical and experimental data suggest an important role of testosterone in sex-related differences in ventricular repolarization. However, studies on effects of testosterone on ionic currents in cardiac myocytes are limited. Methods and Results— We examined effects of testosterone on action potential duration (APD) and membrane currents in isolated guinea pig ventricular myocytes using patch-clamp techniques. Testosterone rapidly shortened APD, with an EC50 of 2.1 to 8.7 nmol/L, which is within the limits of physiological testosterone levels in men. APD shortening by testosterone was mainly due to enhancement of slowly activating delayed rectifier K+ currents (IKs) and suppression of L-type Ca2+ currents (ICa,L), because testosterone failed to shorten APD in the presence of an IKs inhibitor, chromanol 293B, and an ICa,L inhibitor,...
Abstract 15980: Characteristics and Outcomes of Myocardial Infarction With Nonobstructive Coronary Arteries Among 7,015,435 Hospitalizations in California
Authors: Christopher B Khoury, Gregory Nah, Zian H Tseng, Rima Arnaout, Gregory M Marcus, Nisha I Parikh
Journal: Circulation (2016)

Introduction: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is is less well characterized in terms of risk factors and prognosis than AMI with obstructive coronary artery disease (AMI-CAD). Methods: Among 7,015,435 hospitalized adults in California captured by the Healthcare Cost and Utilization Project between 2005-2009, we studied the prevalence of MINOCA and its specific subtypes including coronary vasospasm, coronary artery dissection, Takotsubo cardiomyopathy, hypercoagulable state, and coronary artery anomaly using ICD-9 codes. We used Cox proportional hazards model for major adverse cardiac events (MACE), including MI, heart failure, and death (follow up until 2011) and rehospitalization. Results: 1,585 had MINOCA and 175,809 had AMI-CAD. Among all MINOCA, 46% had coronary artery dissection, 21% had Takotsubo, 14% had a coronary artery anomaly, 13% had coronary vasospasm, and 6% had a hypercoagulable state. Diabetes, hypertension were lower and obesity rates higher in MINOCA ...
Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice
Authors: TsuyoshiHattori, HiroakiShimokawa, MidorikoHigashi, JunkoHiroki, YasushiMukai, KozoKaibuchi, AkiraTakeshita
Journal: Circulation Research (2004)

Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene tr...
Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia
Authors: SebastianoSciarretta, PeiyongZhai, DanShao, YasuhiroMaejima, JeffreyRobbins, MassimoVolpe, GianluigiCondorelli, JunichiSadoshima
Journal: Circulation (2012)

Background—Rheb is a GTP-binding protein that promotes cell survival and mediates the cellular response to energy deprivation (ED). The role of Rheb in the regulation of cell survival during ED has not been investigated in the heart. Methods and Results—Rheb is inactivated during cardiomyocyte (CM) glucose deprivation (GD) in vitro, and during acute myocardial ischemia in vivo. Rheb inhibition causes mTORC1 inhibition, because forced activation of Rheb, through Rheb overexpression in vitro and through inducible cardiac-specific Rheb overexpression in vivo, restored mTORC1 activity. Restoration of mTORC1 activity reduced CM survival during GD and increased infarct size after ischemia, both of which were accompanied by inhibition of autophagy, whereas Rheb knockdown increased autophagy and CM survival. Rheb inhibits autophagy mostly through Atg7 depletion. Restoration of autophagy, through Atg7 reexpression and inhibition of mTORC1, increased cellular ATP content and reduced endoplasmic reticulum stress, th...
Abstract 4301: Mechanisms underlying the inhibitory effect of CRT0066101 on bladder cancer growth in vitro and in vivo
Authors: Quentin Li, Iawen Hsu, Reema Railkar, Thomas Sanford, Piyush K. Agarwal
Journal: Cancer Research (2018)

Abstract CRT0066101 is an inhibitor of protein kinase D with anti-tumor activity in several types of human carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer remain unknown. In this study, we show that CRT0066101 inhibited the proliferation and migration of bladder cancer cells, but had only a marginal effect in human uroepithelial cells, indicating a differential inhibitory effect on cell growth between bladder cancer and normal urothelium. We also demonstrate that CRT0066101 blocked bladder cancer growth in a xenograft flank mouse model. Our cell cycle analysis revealed that CRT0066101 arrested bladder tumor cells at the G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and CDK1 and increases in the levels of p27kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 reduced the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which phosphorylates/ inactivates Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which cause a reduction in CDK1-cyclin B1 activity. Together, these data suggest that CRT0066101 suppresses bladder cancer growth partly through modulating the cell cycle G2 checkpoint and inducing G2-M phase arrest, leading to the blockade of cell cycle progression. Citation Format: Quentin Li, Iawen Hsu, Reema Railkar, Thomas Sanford, Piyush K. Agarwal. Mechanisms underlying the inhibitory effect of CRT0066101 on bladder cancer growth in vitro and in vivo [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 4301.
Cyclic Stretch Controls the Expression of CD40 in Endothelial Cells by Changing Their Transforming Growth Factor–β1 Response
Authors: ThomasKorff, KarinAufgebauer, MarkusHecker
Journal: Circulation (2007)

Background— CD40 is a costimulatory molecule that acts as a central mediator of various immune responses, including those involved in the progression of atherosclerosis. Correspondent to its function, CD40 is present not only on many immune cells, such as antigen-presenting cells and T cells, but also on nonimmune cells, such as endothelial cells. Methods and Results— Ex vivo analyses in mice revealed that CD40 is strongly expressed in distinct venous and capillary but not arterial endothelial cell populations. Therefore, we analyzed to what extent determinants of an arterial environment control CD40 expression in these cells. In vitro studies indicated that the presence of smooth muscle cells or exposure to cyclic stretch significantly downregulates CD40 expression in human endothelial cells. Interestingly, endothelial cells cocultured with smooth muscle cells upregulated CD40 expression in response to cyclic stretch through a transforming growth factor–β1/activin-receptor–like kinase-1 (Alk-1)–dependent...
Abstract 18697: “Forgotten” Cluster with Moderately-impaired LV Diastolic Function Determined by Doppler Echocardiography
Authors: TakuyaHasegawa, MasanoriAsakura, HideakiKanzaki, HiroshiAsanuma, AkiraFunada, TakahiroOhara, YasuoSugano, SatoshiYasuda, HisaoOgawa, ToshihisaAnzai, MasafumiKitakaze
Journal: Circulation (2014)

Background: Left ventricular (LV) diastolic function is mainly determined by the waves of transmitral flow and mitral annular velocity and classified as normal diastolic function, or mild, moderate, and severe diastolic dysfunction. However, it has been known that some subjects are not assigned to any group by the criteria. We investigated the prevalence and severity of the undetermined subjects in the general population. Methods: We studied 1559 community-dwelling subjects without obvious heart diseases or signs of heart failure (mean age, 61±12 years; 576 men, 983 women) who participated in the annual health checkup in a rural Japanese community, Arita-cho. LV diastolic dysfunction was determined with the waves of transmitral flow and mitral annular velocity, using established criteria (Redfield MM, JAMA2003). We investigated the plasma BNP levels in the predetermined and undetermined groups of LV diastolic dysfunction. Results: In this population, 769 subjects (49%) had normal LV diastolic function; 32...