tbuckley/cabot-search huggingface dataset:
Upregulation of Immunoreactive Angiotensin II Release and Angiotensinogen mRNA Expression by High-Frequency Preganglionic Stimulation at the Canine Cardiac Sympathetic Ganglia
Authors: KazushiKushiku, HiromiYamada, KazuhikoShibata, RyokoTokunaga, TakeshiKatsuragi, TatsuoFurukawa
Journal: Circulation Research (2001)

Abstract—The possible involvement of the local angiotensin system in ganglionic functions was investigated in the canine cardiac sympathetic ganglia. Positive chronotropic responses to preganglionic stellate stimulation at high frequencies, after intravenous administration of pentolinium plus atropine, were inhibited by the nonpeptide angiotensin AT1 receptor antagonist forasartan or the angiotensin I–converting enzyme inhibitor captopril, whereas the rate increases elicited by the postganglionic stellate stimulation and norepinephrine given intravenously failed to be inhibited by these antagonists. The levels of endogenous immunoreactive angiotensin II, as determined by radioimmunoassay in the incubation medium of the stellate and inferior cervical ganglia, were increased after the high-frequency preganglionic stimulation of the isolated ganglia. The increment of the peptide was also antagonized by the pretreatment with captopril but not by a chymase inhibitor, chymostatin. The expression of angiotensino...
Abstract 18365: Mechanical Unloading Suppresses Localized Beta-2 Adrenoceptor and L-type Calcium Channel Function in Healthy and Failing Cardiomyocytes
Authors: Peter T Wright, Carla Lucarelli, Jose Sanchez-Alonso, Sean Bello, Giuseppe Faggian, Cesare Terracciano, Julia Gorelik
Journal: Circulation (2017)

Partial mechanical unloading of the healthy left ventricle has been demonstrated to reduce the regularity of t-tubular structures, increase the frequency of calcium sparks and disturb calcium homeo...
Electrophysiological Mechanisms in Successful Radiofrequency Catheter Modification of Atrioventricular Junction for Patients With Medically Refractory Paroxysmal Atrial Fibrillation
Authors: Shih-AnnChen, Shih-HuangLee, Chern-EnChiang, Chin-TaiTai, Tsu-JueyWu, Chen-ChuanCheng, Zu-ChiWen, Chuen-WangChiou, Kwo-ChangUeng, Mau-SongChang
Journal: Circulation (1996)

Background Mechanisms and changes of electrophysiological (EP) characteristics in successful radiofrequency (RF) modification of right midseptal and posteroseptal areas for controlling rapid ventricular response to atrial fibrillation (Af) are not clear. Methods and Results We studied 50 patients with medically refractory paroxysmal Af. Group 1 consisted of 40 patients without dual atrioventricular (AV) node physiology with modification sites located in the mid/posteroseptal area. Of the 40 patients, 36 had successful modification (follow-up of 14±8 months), and 3 had AV block. Late follow-up electrophysiological study (98±10 days) showed pattern 1 (67%) with prolongation of AV node effective refractory period (ERP, ≥40 milliseconds) and Wenckebach block cycle length (WBCL, ≥40 milliseconds); pattern 2 (22%) with prolongation of AH interval (≥20 milliseconds), ERP, and WBCL; and pattern 3 (11%) without any change in AV node conduction parameter. Change in ventricular rate negatively correlated with change...
Defective l-Arginine–Nitric Oxide Pathway in Offspring of Essential Hypertensive Patients
Authors: StefanoTaddei, AgostinoVirdis, PaolaMattei, LorenzoGhiadoni, IsabellaSudano, AntonioSalvetti
Journal: Circulation (1996)

Background Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to investigate whether this abnormality is a primary defect or a consequence of blood pressure increases. Methods and Results In offspring of essential hypertensive patients (n=34) and normotensive subjects (n=30), we evaluated forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg·100 mL−1·min−1), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg·100 mL−1·min−1), an endothelium-independent vasodilator. Minimal forearm vascular resistances also were calculated as the ratio between mean intra-arterial pressure and maximal forearm blood flow induced by forearm ischemia and hand exercise. Vasodilation to acetylcholine was significantly (P<.01) blunted in offspring of hypertensive patients compared with offspring of normotensive subjects, whereas the responses to sodium nit...
Abstract IA17: Pathway dependence and drug synergism in NF1-associated malignant peripheral nerve sheath tumors using the zebrafish model
Authors: Dong Hyuk Ki, Shuning He, A. Thomas Look
Journal: Clinical Cancer Research (2018)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are very aggressive and often metastatic soft tissue sarcomas, which are frequently found in patients who have neurofibromatosis type 1 (NF1). Currently, surgical excision is the only curative therapy for MPNST; however, many patients have unresectable or metastatic tumors at diagnosis and the recurrence rate after surgery is high. Chemotherapy regimens are only partially effective and associated with significant toxicity that can severely reduce quality of life. To establish a preclinical model of this highly malignant tumor, we developed a faithful in vivo MPNST transplantation assay to assess pathway dependence. mCherry-labeled MPNSTs cells were harvested from nf1 and p53 mutant zebrafish and implanted into the pericardial space of embryos at 2 dpf. 24 hours later, we added multiple pathway inhibitors or DMSO vehicle to the fish water and the embryos were incubated for 4 days. Drugs in clinical use for MPNST were tested such as inhibitors of MEK (trametinib), RTK (sunitinib), mTOR (rapamycin), HSP90 (ganetespib), microtubules (vincristine), alkylating agents (cytoxan), XPO I (selinexor), topo II (etoposide), and topo I (topotecan). Of these, only topotecan and selinexor showed significant cytotoxic responses at their MTDs. These two inhibitors were also active in human MPNST cell lines, and we are testing to see if their tumor cell cytotoxic effects are synergistic. Clinical trials of Topo I and XPO I inhibitors have not been reported for MPNST, and our results indicate that these two drugs should be evaluated clinically in patients with this tumor. We are now assessing FDA-approved drugs to identify those that synergize with topotecan and selinexor to induce sustained MPNST cell death and improved survival at tolerable dosages. Our long-range goal is to define active combinations of three or more non-cross resistant drugs that exhibit synergistic and sustained tumor cell cytotoxicity at dosages tolerable to the host. Citation Format: Dong Hyuk Ki, Shuning He, A. Thomas Look. Pathway dependence and drug synergism in NF1-associated malignant peripheral nerve sheath tumors using the zebrafish model [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA17.
Abstract 2949: Synergistic effects of tyrosine kinase inhibitors and conventional chemotherapeutics on canine and human osteosarcoma cells
Authors: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2018)

Abstract Osteosarcoma (OS) is the most common bone tumor in both humans and dogs, and has a nearly ten fold higher incidence in dogs than humans. Despite advances in treatment of other cancers, the overall survival rates for OS have stagnated for the past decades. Therefore, there is a great need to identify novel and effective treatments. In the past few years, several classes of novel small molecules with anti-tumor activities have become available. Among them, we selected tyrosine kinase inhibitors (TKIs) with potential anti-tumor medications to evaluate the effects of treating OS. In our previous studies, two TKIs (sunitinib and sorafenib) showed good growth inhibition effects at low concentrations on three canine OS cell lines (D17, Abrams, and Gracie) and two human OS cell lines (SAOS2 and U2OS) in a series of drug screening assay. In addition to viability, migration, and invasion ability of OS cells were decreased by these two TKIs. Furthermore, we investigated the effect of combing one of the TKIs with current chemotherapeutics for OS. We determined the combination index to assess whether sorafenib and sunitinib have synergistic effects with conventional chemotherapeutics including cisplatin, carboplatin, or doxorubicin. Data from our cell lines point to synergistic effects of sorafenib combined with doxorubicin, but not when combined with cisplatin or carboplatin in both human and canine OS. Combination studies with sunitinib are ongoing. Based on current findings, clinical trials using combination of doxorubicin and sorafenib in proof of concept studies in dogs are warranted. These studies can be carried out relatively quickly in dogs where case load is high, and in turn, provide useful data for initiation of clinical trials in humans. Citation Format: Ya-Ting Yang, Vilma Yuzbasiyan-Gurkan. Synergistic effects of tyrosine kinase inhibitors and conventional chemotherapeutics on canine and human osteosarcoma 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 2949.
Vessel Size and Long-Term Outcome After Coronary Stent Placement
Authors: ShpendElezi, AdnanKastrati, Franz-JosefNeumann, MartinHadamitzky, JosefDirschinger, AlbertSchömig
Journal: Circulation (1998)

Background—The role of coronary stenting in the treatment of patients with small vessels is not well defined. The purpose of this study was to investigate the influence of vessel size on long-term clinical and angiographic outcome after coronary stent placement. Methods and Results—The study comprised 2602 patients with successful stent implantation for symptomatic coronary artery disease. Patients were subdivided into 3 equally sized groups (tertiles) according to vessel size, with respective ranges of  3.2 mm. Event-free survival at 1 year was 69.5% in the group with smaller vessels, 77.5% in the second group, and 81% in the group with larger vessels (P<0.001). Late lumen loss was similar between the 3 groups (1.12±0.73, 1.12±0.79, and 1.09±0.88 mm, respectively). Angiographic restenosis rate was significantly higher in the small-vessel group (38.6%, 28.4%, and 20.4% in groups 1, 2, and 3, respectively; P<0.001). The analysis identified subgroups with different risk for restenosis ...
Abstract 135: The Association of Preshock Pause and Survival from Out-of-Hospital Cardiac Arrest
Authors: Tyler Vadeboncoeur, Ryan Anne Murphy, John Tobin, Mark Venuti, Daniel Spaite, Madalyn Karmooz, Annemarie Silver, Pedro Roque, Uwe Stolz, Bentley Bobrow
Journal: Circulation (2012)

Objective: Preshock pause (PSP_time from last chest compression [CC] to defibrillation) is believed to be an important component of CPR quality, but the relationship between PSP and survival is unknown. We sought to determine if a dedicated intervention to improve prehospital CPR quality and minimize PSPs would result in a shortened preshock interval and improve survival from out-of-hospital cardiac arrest (OHCA). Methods: Data were extracted from prehospital care reports and defibrillators (E Series, ZOLL) of 2 EMS agencies (combined population-500,000) participating in a CPR quality improvement program. Consecutive non-traumatic adult OHCA of presumed cardiac etiology were included. Phase 1 (P1): 19 months of baseline data with real-time audiovisual feedback (RTAVF) disabled (9/08-3/10). Interventions: 1) Scenario-based training of ∼450 EMTs, 2) RTAVF enabled, 3) activation of “Charging During Compressions” feature, 4) EMT post-code debriefings. Phase 2 (P2):16 months immediately following implementatio...
Abstract 1750: Inducing therapeutic lymphangiogenesis for potentiating cancer immunotherapy in melanoma
Authors: Lambert Potin, Lea Maillat, Priscilla S. Briquez, Jeffrey A. Hubbell, Melody A. Swartz
Journal: Cancer Research (2018)

Abstract Tumor-associated lymphangiogenesis is well known to promote metastasis and to correlate with poor prognosis in melanoma and other cancers, yet its functional roles in antitumor immunity had remained largely unexplored. In a recent study, we investigated the role of the vascular endothelial growth factor C (VEGF-C)—the main driver of lymphangiogenesis—in regulating antitumor immune response. We showed that in the B16 F10 injectable melanoma model, VEGF-C inhibition prevented T cells from infiltrating the tumor and reduced the efficacy of immunotherapies. Here, we sought to extend this concept to exploit the immunologic benefits of VEGF-C for therapeutic applications. We engineered a VEGF-C variant with an extracellular matrix-binding domain (MB-VEGF-C) allowing retention into the microenvironment after intratumoral injection. MB-VEGF-C induced increased lymphatic vasculature in tumors without reducing tumor growth rate. In an autochthonous melanoma model with reduced immune infiltrates, MB-VEGF-C intratumoral injections promoted the infiltration of cross-presenting DCs, as well as CD8+ and CD4+ T cells. Crucially, in these tumors that are normally unresponsive to immune checkpoint blockade (ICB), we could restore the responsiveness to ICB by delivering MB-VEGF-C together with immune adjuvants. Taken together, our findings suggest that VEGF-C and tumor-associated lymphangiogenesis, albeit promoting metastasis, can also be exploited to promote a T cell-inflamed microenvironment and to subsequently potentiate immunotherapies. Citation Format: Lambert Potin, Lea Maillat, Priscilla S. Briquez, Jeffrey A. Hubbell, Melody A. Swartz. Inducing therapeutic lymphangiogenesis for potentiating cancer immunotherapy 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 1750.
Abstract 17793: Importance of Preoperative Pulmonary Rehabilitation in Patients With Thoracic Aortic Diseases
Authors: Masashi Takeuchi, Yasuharu Matsumoto, Shunsuke Kawamoto, Kiichirou Kumagai, Hirokazu Amamizu, Kazuma Ohyama, Hironori Uzuka, Kensuke Nishimiya, Masahiro Kohzuki, Yoshikatsu Saiki, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Preoperative pulmonary rehabilitation (PR), in addition to post-operative PR, is known to have beneficial effects in general. However, it remains to be examined whether preoperative PR is also safe and effective for patients with thoracic aortic disease. Hypothesis: We assessed the hypothesis that the incidences of pulmonary complications were reduced in the PR group compared with the control group. Methods: We examined 128 consecutive patients who underwent elective surgery for thoracic aortic disease (aortic aneurysm in 88 and aortic dissection in 40) and post-operative PR in our hospital since January 1, 2010. Among them, pre-operative PR [20 min/day, mean 12 days, active cycle breathing technique (ACBT) contains a cycle of including breathing control, thoracic expansion, and forced expansion technique] was performed in 77 patients (PR group) on the basis of ACBTs with careful monitoring of blood pressure. All patients received standard cardiovascular rehabilitation after the surgery. Resul...
Recanalization Therapies in Acute Ischemic Stroke Patients
Authors: David J. Seiffge, Robbert-JanVan Hooff, Christian H. Nolte, Yannick Béjot, Guillaume Turc, Benno Ikenberg, Eivind Berge, Malte Persike, Nelly Dequatre-Ponchelle, Daniel Strbian, Waltraud Pfeilschifter, Andrea Zini, Arnstein Tveiten, Halvor Næss, Patrik Michel, Roman Sztajzel, Andreas Luft, Henrik Gensicke, Christopher Traenka, Lisa Hert, Jan F. Scheitz, Gian Marco De Marchis, Leo H. Bonati, Nils Peters, Andreas Charidimou, David J. Werring, Frederick Palm, Matthias Reinhard, Wolf-Dirk Niesen, Takehiko Nagao, Alessandro Pezzini, Valeria Caso, Paul J. Nederkoorn, Georg Kägi, Alexander von Hessling, Visnja Padjen, Charlotte Cordonnier, Hebun Erdur, Philippe A. Lyrer, Raf Brouns, Thorsten Steiner, Turgut Tatlisumak, Stefan T. Engelter
Journal: Circulation (2015)

We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC).This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICHany), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICHECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICHNINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8-22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1-1.6). ICHany was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICHECASS-II and sICHNINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences.IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.
Microparticles harbouring Sonic hedgehog morphogen improve the vasculogenesis capacity of endothelial progenitor cells derived from myocardial infarction patients
Authors: Carlos Bueno-Betí, Susana Novella, Raffaella Soleti, Ana Mompeón, Luisa Vergori, Juan Sanchís, Ramaroson Andriantsitohaina, María Carmen Martínez, Carlos Hermenegildo
Journal: Cardiovascular Research (2018)

Endothelial progenitor cells (EPC) play a role in endothelium integrity maintenance and regeneration. Decreased numbers of EPC or their impaired function correlates with an increase in cardiovascular events. Thus, EPC are important predictors of cardiovascular mortality and morbidity. Microparticles carrying Sonic hedgehog (Shh) morphogen (MPShh+) trigger pro-angiogenic responses, both in endothelial cells and in ischaemic rodent models. Here, we propose that MPShh+ regulates EPC function, thus enhancing vasculogenesis, and correcting the defects in dysfunctional EPC obtained from acute myocardial infarction (AMI) patients.The mechanisms underlying Shh pathway function and nitric oxide (NO) production in EPC were evaluated. MPShh+ increased both the in vitro and in vivo vasculogenic capacity of EPC isolated from adult human peripheral blood samples. MPShh+ treatment significantly increased the expression of Shh signalling pathway genes (PTCH1, SMO, and GLI1) and masters of pro-angiogenic genes (NOS3, VEGFA, KDR, and KLF2) in EPC. Moreover, MPShh+ increased both the protein expression and activity of eNOS, resulting in increased NO production. Most importantly, MPShh+ improved the vasculogenic capacity of EPC from AMI patients to levels similar to that of EPC from healthy patients. All these effects were due to the activation of Shh pathway.MPShh+ increase both the vasculogenesis of EPC and their capacity to produce NO, including EPC from patients who have recently suffered an AMI. This study emphasizes MPShh+ and EPC as potential therapeutic tools for improving vascular regeneration as a treatment for cardiovascular ischaemic disease.
Abstract 215: The Redox Activation of DUSP4 by N-Acetyl Cysteine Protects Endothelial Cells and the Myocardium against Oxidative Damage
Authors: Chun-AnChen, AlmaBarajas-Espinosa, ArielBasye, HaixuYan, ErinJesse, DavidQuan
Journal: Circulation Research (2014)

Background: Redox imbalance is the primary cause for endothelial dysfunction (ED), obstructed blood flow, and subsequent heart attack and failure. Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of glutathione (GSH), the primary reducing source, can significantly regulate cell function via reversible protein thiol modification. N-Acetyl cysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. Methods: We employed EPR spin-trapping, HPLC, fluorescent microscopy, immunoblotting, and qPCR of both in vitro and ex vivo experiments using either cultured cells or the Langendorff heart preparation. Results: NAC treatment increases NO generation from endothelial cells, as well as the enzyme and cofactor responsible for its production, ie eNOS and BH4. Interestingly, NAC treatment also increased the expression of DUSP4,...
Abstract 1980: S116836 overcomes BCR-ABL T315I mutation mediated imatinib resistance in chronic myeloid leukemia
Authors: Pranav Gupta, Guannan Zhang, Anna Maria Barbuti, Ke Ding, Jingxuan Pan, Brian J. Druker, Zhe-Sheng Chen
Journal: Cancer Research (2018)

Abstract Chronic Myeloid Leukemia (CML) is largely caused by the Philadelphia (Ph) chromosome carrying the Break point Cluster Region-Abelson (BCR-ABL) oncogene. Imatinib is a BCR-ABL-targeted therapy and considered the standard of care in CML management. Resistance to imatinib therapy often develops because of mutations in the BCR-ABL kinase domain. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer activity against BCR-ABL expressing BaF3 cells. S116836 shows potent activity against wild-type and T315I mutated BaF3 cells as compared with imatinib. S116836 inhibited the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. S116836 inhibited the mRNA expression of BCR-ABL in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 increased the cell population in the G0/G1 phase of the cell cycle, induced apoptosis and elevated ROS production in both BaF3/WT and BaF3/T315I cells. Moreover, S116836 inhibited tumor growth in BaF3/WT and BaF3/T315I tumor xenografts. Taken together, our results indicate that S116836 exhibits anti-proliferative effects and inhibits the imatinib-resistant T315I BCR-ABL mutation. S116836 may be a novel drug candidate for overcoming the resistance to imatinib in CML patients. Keywords: S116836, Chronic myeloid leukemia, BCR-ABL, T315I, Resistance Citation Format: Pranav Gupta, Guannan Zhang, Anna Maria Barbuti, Ke Ding, Jingxuan Pan, Brian J. Druker, Zhe-Sheng Chen. S116836 overcomes BCR-ABL T315I mutation mediated imatinib resistance in chronic myeloid leukemia [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 1980.