tbuckley/cabot-search huggingface dataset:
Abstract 12584: Combined Treatment With Irbesartan and Amlodipine Potently Prevents Acute Myocardial Infarction in Subtotally Nephrectomized Triple Nitric Oxide Synthases-Deficient Mice
Authors: MasatoTsutsui, TaroUchida, YumiFuruno, AkihideTanimoto, MikaKina-Tanada, HaruakiKubota, MayukoSakanashi, ToshihiroMatsuzaki, KatsuhikoNoguchi, JunkoNakasone, YusukeOhya, NobuyukiYanagihara, HiroakiShimokawa, MasahitoTamura, YutakaOtsuji
Journal: Circulation (2015)

Background: Since there are few experimentally useful models that develop acute myocardial infarction (AMI), research and development of therapeutic strategies for preventing AMI have made little progress. We have recently demonstrated that 2/3 nephrectomized (NX) triple nitric oxide synthases (NOSs)-deficient mice cause sudden death due to AMI as early as 4 months after the surgery, succeeding in the establishment of an experimentally useful AMI model (JMCC 2014). In this study, we examined the effects of an angiotensin II type 1 receptor blocker, irbesartan (irbe), and a calcium channel antagonist, amlodipine (amlo), in this model. Method and Results: The 2/3NX triple NOSs-/- mice were treated with irbe (50 mg/ml/day in chow); amlo (250 mg/ml in drinking water); a combination of both; or an anti-hypertensive agent, hydralazine (0.25 mg/ml in drinking water) for 6 months (n=20-49). We used the clinical therapeutic dosage. In this model, the mono-treatment with irbe or amlo significantly reduced the incid...
Abstract A26: Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma
Authors: Pablo Angulo, Katherine Chastain, Dharmalingam Subramaniam, Shrikant Anant
Journal: Clinical Cancer Research (2018)

Abstract Objective: Osteosarcoma (OS) is the most common pediatric bone cancer worldwide with an annual US incidence of 800. Chemotherapy and surgery have resulted in a marginal increase in survival of localized OS. However, that same treatment regimen has not been as successful for improving metastatic OS, as it yields an abysmal 5-year overall survival of less than 30% in patients afflicted with the disease. There have not been new successful standardized treatment agents in the last 2 decades for OS. Current standard practice still implements the same chemotherapeutic agents: cisplatin, doxorubicin, and methotrexate. These nonspecific agents have failed to yield optimal survival in metastatic OS patients. Hence, there is a need to utilize different agents that can specifically target signaling pathways involved in the pathogenesis of OS. One such pathway that has been found to be instrumental in the pathogenesis of OS is the JAK/STAT pathway, and the antipsychotic medication pimozide appears to be able to halt OS growth through inhibiting this pathway. Herein, we investigated the effects of pimozide on OS cancer growth and elucidated its mechanistic action through STAT signaling pathway. Methods: Human OS cell lines KHOS, MG63, and SJSA cell lines and normal osteoblast cells were used in the study. The effects of pimozide on cell proliferation were assessed by hexosaminidase and clonogenicity assays. Effects of pimozide on stem cells were evaluated by colonosphere formation. Furthermore, the effect of pimozide on OS cells was evaluated by live cell fluorescent staining. Western blot was utilized to evaluate the effect on STAT protein expression. Results: Pimozide treatment resulted in a dose- and time-dependent inhibition of proliferation and colony formation in all three osteosarcoma cell lines but not in osteoblast cells. It induces caspase 3 and 7 activity. Pimozide also showed reduced live cell fluorescent staining. Pimozide significantly reduced the number and size of spheroid formation. In addition, pimozide inhibits OS stem cell marker protein CD44 expression. Moreover, pimozide treatment decreased the expression of STAT5 signaling proteins on Western blot, which suggests that pimozide inhibits OS growth through STAT signaling pathway. Conclusion: Together, these data suggest that pimozide inhibits OS cancer growth by inhibiting the STAT signaling pathway. Pimozide could serve as a potential therapeutic agent for OS. Citation Format: Pablo Angulo, Katherine Chastain, Dharmalingam Subramaniam, Shrikant Anant. Pimozide, an antipsychotic derivative, targets the STAT signaling pathway in osteosarcoma [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 A26.
Myelofibrosis Treatment Algorithm 2018
Authors: Ayalew Tefferi, Paola Guglielmelli, Animesh Pardanani, Alessandro M. Vannucchi
Journal: Blood Cancer Journal (2018)

Abstract Two novel prognostic systems for primary myelofibrosis (PMF) were recently unveiled: GIPSS (genetically inspired prognostic scoring system) and MIPSS70 (mutation-enhanced international prognostic scoring system for transplant-age patients). GIPSS is based exclusively on genetic markers: mutations and karyotype. MIPSS70 includes mutations and clinical risk factors. In its most recent adaptation, the prognostic value of MIPSS70 has been bolstered by the inclusion of a three-tiered cytogenetic risk stratification and use of hemoglobin thresholds that are adjusted for sex and severity (MIPSS70+ version 2.0). GIPSS features four, MIPSS70 three, and MIPSS70+ version 2.0 five risk categories. MIPSS70 is most useful in the absence of cytogenetic information. MIPSS70+ version 2.0 is more comprehensive than MIPSS70 and is the preferred model in the presence of cytogenetic information. Both MIPSS70 and MIPSS70+ version 2.0 require an online score calculator ( http://www.mipss70score.it ). GIPPS offers a lower complexity prognostic tool that reliably identifies candidates for allogeneic stem cell transplant (GIPSS high-risk disease) or long-term observation with little or no therapeutic intervention (GIPSS low-risk disease). Ultimately, we favor a step-wise prognostication approach that starts with GIPSS but also considers MIPSS70+ version 2.0 for confirming the most appropriate treatment approach for the individual patient.
Abstract 4197: Sulforaphane suppresses metastasis via autophagic degradation of cathepsin S in oral cancer cells
Authors: Chiao-Wen Lin, Chang-Tai Chen, Shun-Fa Yang
Journal: Cancer Research (2018)

Abstract Sulforaphane has been demonstrated to exert numerous biological effects, such as neuroprotective, anti-inflammatory, and anticancer effects. However, the detailed effects of sulforaphane on human oral cancer cell metastasis and the underlying mechanisms remain unclear. In this study, we observed that sulforaphane attenuated SCC-9 and SCC-14 cell motility and invasiveness by reducing cathepsin S expression. Moreover, sulforaphane increased microtubule-associated protein 1 light chain 3 (LC3) conversion, and the knockdown of LC3 by siRNA increased cell migration ability. Mechanistically, sulforaphane inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK1/2) pathway, and blocking of the ERK1/2 pathway reversed autophagy-mediated cell motility and CTSS inhibition. In conclusion, sulforaphane exhibits antimetastatic activity against oral cancer cells by repressing cathepsin S through the ERK1/2 signaling pathway. Thus, cathepsin S and LC3 may be new targets for oral cancer treatment. Citation Format: Chiao-Wen Lin, Chang-Tai Chen, Shun-Fa Yang. Sulforaphane suppresses metastasis via autophagic degradation of cathepsin S in oral 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 4197.
Abstract 2160: MEN1611, a novel α-selective PI3K inhibitor in solid tumors
Authors: Giuseppe Merlino, Alessio Fiascarelli, Mario Bigioni, Alessandro Bressan, Clelia Irrissuto, Andrea Pellacani, Maurizio Scaltriti, Monica Binaschi
Journal: Cancer Research (2018)

Abstract The PI3K pathway regulates various cellular processes such as proliferation, growth, apoptosis and cytoskeletal rearrangement. This pathway is frequently de-regulated and considered an oncogenic driver in human cancer. In most solid tumors, the activation of the PI3K pathway is induced by mutations of the catalytic subunit PI3Kα, present in approximately 20% to 50% of breast cancer, 14% of colorectal cancer and in 5-10% of NSCLC. Besides being an actionable target, the PI3K pathway is implicated in de novo and acquired treatment resistant in various tumor types treated with targeted therapy. As a matter of fact, the most interesting antitumor activity with PI3K inhibitors has been observed in combination. Here, we present MEN1611 (previously PA799), a PI3-kinase inhibitor with a peculiar biochemical profile targeting with high inhibition potency the mutated forms of PI3Kα and PI3Kγ. In the current study we demonstrate the anticancer activity and the pharmacodynamic effects of MEN1611 as monotherapy or in combination with targeted therapies in both xenograft and PDX models of breast cancer and in colorectal cancer and in NSCLC models, all with defined genetic profiles. MEN1611, at a clinically relevant dose, showed good antitumor activity in combination with targeted therapy agents against breast cancer, colorectal cancer and NSCLC models bearing PI3Kα mutations. A reduced activity was instead observed when the tumor models were wild type for PI3Kα or had low levels of PTEN. The antitumor activity of MEN611 was supported by its pharmacodynamic activity. In all the models, both AKT and S6 phosphorylation, markers of PI3K inhibition, were significantly inhibited upon treatment. In agreement with the biochemical profile of the drug, in PTEN null xenograft models where the tumor driver is the PI3K β-isoform, we observed lower effects in term of antitumor activity and of molecular inhibition of the pathway. Last, MEN1611 induction of hyperglycemia and insulin release was studied in the tumor models at clinical relevant dose as a marker of class-effect toxicity. MEN1611 showed significant antitumor activity in combination with other targeted therapies in breast, colon and NSCL cancer PI3Kα mutant models. Our results support the evidence that MEN611 is a PI3Kα specific inhibitor and provided the basis for the planned phase IB/II. Citation Format: Giuseppe Merlino, Alessio Fiascarelli, Mario Bigioni, Alessandro Bressan, Clelia Irrissuto, Andrea Pellacani, Maurizio Scaltriti, Monica Binaschi. MEN1611, a novel α-selective PI3K inhibitor in solid tumors [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 2160.
Abstract 16588: A Conductive Biomaterial Patch to Repair a Cardiac Defect
Authors: Sheng He, Hui-Fang Song, Jun Wu, Richard D Weisel, Ren-Ke Li
Journal: Circulation (2016)

Introduction: Both stable and biodegradable biomaterials have been used to repair cardiac defects or stabilize the myocardial infarct after an MI. However, none of these biomaterials conducts elect...
Abstract 973: MEKK3 sustains EMT and stemness in pancreatic cancer by regulating YAP and TAZ transcriptional activity
Authors: Geny Piro, Raffaela Santoro, Marco Zanotto, Carmine Carbone, Giampaolo Tortora, Davide Melisi
Journal: Cancer Research (2018)

Abstract Background: Pancreatic cancer (PC) is one of the most threatening and poorly understood human malignancies. MEKK3 (MAP3K3) is an intracellular serine/threonine kinase activated by different signaling pathways, including IL1, TNFα and TLR8, which regulates in turn NF-κB, JNK and p38 activation.The transcriptional regulators Yes Associated Protein (YAP) and transcriptional coactivator with a PDZ binding domain (TAZ) are central determinants of malignancy and have been identified as a critical oncogenic effectors of KRAS in pancreatic cancer. We hypothesized that MEKK3 could sustain pancreatic cancer by inducing YAP/TAZ oncogenic activities. Methods: MEKK3 was knocked-out (KO) in AsPC1, Panc1, and MDA-Panc28 PC cell lines by CRISPR/Cas9. The expression of MEKK3, E-cadherin, YAP/TAZ and their target genes was measured by both Western blot and qPCR. Cell migration was assessed by transwell and wound healing assays. Stemness was measured by spheroid formation and percentage of CD44+/CD24+/EpCAM+ cancer stem cells (CSC). Effects of MEKK3 KO was evaluated in vivo in an orthotopic nude mouse model with GFP-expressing Panc1 PC cells. Expression of YAP/TAZ and their target genes in tumor samples was measured by IHC. Results: MEKK3 KO resulted in the reversion of both Epithelial-to-Mesenchymal Transition (EMT) and cell migration, as well as in the impairment of cell proliferation. More interestingly, the size of 3D colonies arising from MEKK3 KO cell lines was smaller than the ones formed by their respective controls, due to a reduced percentage of CD44+/CD24+/EpCAM+ CSC. In MEKK3 KO cells, the recruitment of YAP/TAZ onto the promoters of their target genes was significantly impaired and this paired with a reduction of the expression of the same genes. In nude mice, MEKK3 KO significantly reduced tumor growth and prolonged overall survival. Conclusions: Our study is the first to demonstrate that genetic silencing of MEKK3 is a valid approach to revert in vivo the aggressiveness of PC by modulating YAP and TAZ transcriptional activities. Inhibition of MEKK3 could represent an exciting therapeutic strategy for the treatment of PC, which should be warranted further development. Citation Format: Geny Piro, Raffaela Santoro, Marco Zanotto, Carmine Carbone, Giampaolo Tortora, Davide Melisi. MEKK3 sustains EMT and stemness in pancreatic cancer by regulating YAP and TAZ transcriptional 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 973.
Antisense Oligodeoxynucleotides Directed Against Kv1.5 mRNA Specifically Inhibit Ultrarapid Delayed Rectifier K+ Current in Cultured Adult Human Atrial Myocytes
Authors: JianlinFeng, BarbaraWible, Gui-RongLi, ZhiguoWang, StanleyNattel
Journal: Circulation Research (1997)

Abstract Several cloned K+ channel subunits are candidates to underlie macroscopic currents in the human heart, but direct evidence bearing on their role is lacking. The Kv1.5 K+ channel subunit has been suggested to play a potential role in human cardiac ultrarapid delayed rectifier (IKur) and transient outward (Ito) currents. To evaluate the role of proteins encoded by the Kv1.5 gene, we incubated cultured human atrial myocytes for 48 hours in medium containing antisense phosphorothioate oligodeoxynucleotides directed against octodecameric segments of the Kv1.5 mRNA coding sequence, the same concentration of homologous oligodeoxynucleotides with four mismatch mutations, or vehicle (control group). Cells exposed to antisense showed a highly significant (≈50%) reduction in IKur, whether measured by step current at the end of a 400-millisecond depolarizing pulse, tail current at −20 mV, or current sensitive to a concentration of 4-aminopyridine (50 μmol/L) that is highly selective for IKur, compared with c...
Abstract 4137: Inhibition of protein synthesis with polyamine depletion in high-risk neuroblastoma
Authors: Andrea T. Flynn, Kangning Liu, Annette Vu, Michael D. Hogarty
Journal: Cancer Research (2018)

Abstract The MYC family of oncogenes coordinately deregulate cellular programs that link cell cycle progression with the requisite biomass and energy creation. Neuroblastoma is a MYC-driven, commonly lethal pediatric tumor, with a high proportion of tumors containing MYCN amplification. Polyamine synthesis is a pathway downstream of MYC, with polyamines functioning, in part, to support protein synthesis. ODC1 encodes ornithine decarboxylase, the rate-limiting enzyme in polyamine synthesis, and we found that ODC1 is co-amplified with MYCN in a subset of high-risk neuroblastomas (~8%). Difluoromethylornithine (DFMO) is an irreversible inhibitor or ornithine decarboxylase and is an approved agent for the treatment of Trypanosomiasis. We have previously shown that DFMO inhibits tumor progression and synergizes with chemotherapy in murine mouse models of neuroblastoma, and we postulate that inhibition of protein synthesis is a predominant mechanism of anti-tumor activity. The effects of polyamine depletion on specific components of protein translational machinery have yet to be defined. Here, we show inhibition of global protein synthesis of up to 90% after treatment with various concentrations of DFMO in vitro, with a larger decrease in protein synthesis generally correlating with the presence of MYCN amplification. We found that colony formation is inhibited at DFMO exposures as low as 150 to 500 μM DFMO, which are achievable concentrations in adults based on previous clinical trials. We also show via isoelectric focusing that treatment of neuroblastoma cells in vitro with DFMO leads to a marked decrease in the proportion of hypusinated, or active, eIF5A (an elongation factor important in translation of polyproline stretches and possibly broader influence on translation initiation). To interrogate influences of polyamine depletion on the cap-dependent translation eIF4F complex, we evaluated for changes in the phosphorylation of 4E-BP1 in DFMO treatment conditions, though no changes in phosphorylation were seen compared to controls. Studies to further elucidate the protein synthetic components affected by polyamine depletion are ongoing, as are studies to assess for selective effects of DFMO on polyproline-containing proteins via eIF5A. Further elucidation of the mechanisms of DFMO activity will identify opportunities for drug synergy and provide a responder hypothesis to test in upcoming pivotal Phase 2 and 3 clinical trial of DFMO in the treatment of neuroblastoma. Citation Format: Andrea T. Flynn, Kangning Liu, Annette Vu, Michael D. Hogarty. Inhibition of protein synthesis with polyamine depletion in high-risk neuroblastoma [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 4137.
Abstract 9432: Febuxostat -A Xanthine Oxidase Inhibitor- May Improve Cardiorenal Interaction: A Randomized Controlled Pilot Study
Authors: ShigemasaTani, AtsuhikoTakahashi, KenNagao, AtsushiHirayama
Journal: Circulation (2014)

Introduction: There is growing evidence of an association between high uric acid (UA) levels and cardiovascular disease. However, little data is available about the mechanism by which UA metabolism affects cardiorenal interaction, which leads to cardiovascular disease. Febuxostat, a selective xanthine oxidase inhibitor, was approved in 2012 in Japan not only for the treatment of patients with only gout, but also for those with only hyperuricemia. Hypothesis: We hypothesized that febuxostat might modify cardiorenal interactions by suppressing the renin-aldosterone system and improving the renal function in hypertensive hyperuricemic patients. Methods: We conducted a 6-month, prospective, randomized, open-label study in which we classified hypertensive hyperuricemic patients to either a febuxostat group (n = 30) or a control group (n = 30). The serum UA level of the patients was monitored, and the dose of febuxostat was adjusted to maintain the serum UA level < 6.0 mg/dL. Results: In the febuxostat group, t...
Erratum: Corrigendum: MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis
Authors: Changsheng Du, Chang Liu, Jiuhong Kang, Guixian Zhao, Zhiqiang Ye, Shichao Huang, Zhenxin Li, Zhiying Wu, Gang Pei
Journal: Nature Immunology (2010)
Abstract 8969: Female Sex Is Associated With Increased Mortality After Pediatric Cardiac Surgery
Authors: Lazaros Kochilas, Jeffrey Vinocur, Jeremiah Menck, James St. Louis
Journal: Circulation (2011)

Surgical mortality for congenital heart defects is affected by several center and patient specific factors. The role of patient's sex as risk factor for death after pediatric cardiac surgery is disputed. We used 1982-2007 outcome data from the Pediatric Cardiac Care Consortium, a large multi-center clinical database to examine whether sex represents a prognostic factor for mortality after pediatric cardiac surgery. Hierarchical multivariate logistic regression analysis was used to determine the odds ratio (OR) of death for females vs. males after cardiac surgery in children (&lt;18 years old) adjusting for RACHS-1 risk category, patient's age and weight at operation (neonates and infants &lt; 2.5 kg, neonates &gt; 2.5 kg, infants &gt; 2.5 kg, children 1-5y, 6-12y, 13-18y), and 5-year time period of operation. Kaplan-Meier survival curves were generated to examine survival between females and males. After excluding cases without defined risk category or from years with incomplete data, 70,595 patients with 85,023 operations (53.9% males) were included in the analysis. The unadjusted OR for death between females and males was not statistically significant (OR 0.98, 95% CI 0.92-1.04). Males were more likely than females to have cardiac surgery of higher severity and as a neonate, both associated with higher risk of postsurgical mortality. After adjustment, female sex was associated with higher odds ratio (OR) of postoperative death (OR 1.18; 95% CI: 1.11-1.26, p&lt;0.0001). The sex effect was restricted to neonates (OR 1.29, 95% CI 1.15-1.45, p&lt;0.0001) and adolescents (OR 1.6, 95% CI 1.04-2.47, p=0.0342), and to more complex operations (risk categories 4-6 vs. 1-3 OR 1.28, 95% CI 1.14-1.43, p&lt;0.0001). Kaplan-Meier survival curves after surgery demonstrated that the major separation between the survival curves occurs within one day of the operation and the survival curves are approximately parallel after the first day. Conclusions: Female sex is associated with increased risk of early mortality after pediatric cardiac surgery. The risk is age- and risk category-specific affecting mostly neonates and adolescents undergoing higher risk procedures likely to require prolonged exposure to cardiopulmonary bypass.
Sustained Benefit at 2 Years of Primary Femoropopliteal Stenting Compared With Balloon Angioplasty With Optional Stenting
Authors: MartinSchillinger, SchilaSabeti, PetraDick, JasminAmighi, WolfgangMlekusch, OliverSchlager, ChristianLoewe, ManfredCejna, JohannesLammer, ErichMinar
Journal: Circulation (2007)

Background— Primary stenting with self-expanding nitinol stents of the superficial femoral artery yielded improved morphological and clinical results compared with balloon angioplasty with optional stenting until 12 months in a randomized controlled trial. We now report 2-year data on restenosis and clinical outcomes of these patients. Methods and Results— Of 104 patients with chronic limb ischemia and superficial femoral artery obstructions, 98 (94%) could be followed up until 2 years after intervention for occurrence of restenosis (>50%) by duplex ultrasound and for clinical and hemodynamic outcome by treadmill walking distance and ankle brachial index. Restenosis rates at 2 years were 45.7% (21 of 46) versus 69.2% (36 of 52) in favor of primary stenting compared with balloon angioplasty with optional secondary stenting by an intention-to-treat analysis (P=0.031). Consistently, stenting (whether primary or secondary; n=63) was superior to plain balloon angioplasty (n=35) with respect to the occurrence o...
Mitohormesis in Mice via Sustained Basal Activation of Mitochondrial and Antioxidant Signaling
Authors: Carly S. Cox, Sharen E. McKay, Marissa A. Holmbeck, Brooke E. Christian, Andrew C. Scortea, Annie J. Tsay, Laura E. Newman, Gerald S. Shadel
Journal: Cell Metabolism (2018)