tbuckley/cabot-search huggingface dataset:
Abstract 3709: Characterization, in vitro and in vivo efficacy studies of docetaxel trastuzumab stealth immunoliposome in human breast cancer models
Authors: Anne Rodallec, Jean Michel Brunel, Stephane Robert, Sarah Giacometti, Ariel Savina, Fanny Bouquet, Bruno Lacarelle, Joseph Ciccolini, Raphaelle Fanciullino
Journal: Cancer Research (2018)

Abstract In HER2-positive breast cancer, the Trastuzumab + Docetaxel doublet has a significant efficacy but is hampered by frequent toxicities that could be addressed with nanoparticles. We have developed an Antibody-Nano Conjugate (ANC), combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab. This entity is expected to improve the efficacy/toxicity balance of this doublet, by improving trafficking and delivery to the tumors. ANCs were synthesized using thin-film method and trastuzumab was grafted via sulfydryl groups on maleimide polyethylene glycol. Two compositions (ANC-1 and ANC-2) were tested and compared (i.e., size, morphology, encapsulation rate, engrafting rate, and stability). Antiproliferative activity was tested on a panel of human breast cancer models ranging fromHER2-negative (MDA-MB-231) to HER2-positive (MDA-MB-453) or -overexpressing (SKBR3), both on 2D and spheroid models. Biodistribution, efficacy and survival were tested in MDAMB-231 and MDA-MB-453 bearing nude mice. ANC-1 presented a greater size (140 ± 3 nm), docetaxel encapsulation rate (73 ± 6 %) and stability as compared with ANC-2. In vitro, both ANCs were found to be more efficient than standard docetaxel + trastuzumab, with a better performance for ANC-1. In vivo, ANC-1 accumulated better in tumors, resulting in a higher reduction in tumor growth (i.e. &amp;gt;+36%) and prolonged survival (i.e. &amp;gt;+33%) as compared with standard treatment. Both in vitro and in vivo results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models. Of note, although modest, even Her2- model (i.e., MDA231) was found to benefit from the nanoparticle. Citation Format: Anne Rodallec, Jean Michel Brunel, Stephane Robert, Sarah Giacometti, Ariel Savina, Fanny Bouquet, Bruno Lacarelle, Joseph Ciccolini, Raphaelle Fanciullino. Characterization, in vitro and in vivo efficacy studies of docetaxel trastuzumab stealth immunoliposome in human breast cancer models [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 3709.
Abstract 1902: Potential role of DYRK family kinases in harmine-induced apoptosis in neuroblastoma
Authors: Katie L. Uhl, Chad R. Schultz, Dirk Geerts, Andre S. Bachmann
Journal: Cancer Research (2018)

Abstract The purpose of this study was to determine the effect of the natural product Harmine in human neuroblastoma (NB). NB is an early childhood malignancy arising from the developing peripheral nervous system. In up to 25% of cases MYCN gene amplification is correlated to high tumor stage and poor patient prognosis. High stage NB relapses frequently in spite of multimodal therapy and is then virtually untreatable. There is a clear need for specific, novel therapeutics. Harmine is a tricyclic β-carboline alkaloid from the harmal plant with cytostatic and cytotoxic effects on tumor cells. It is capable of blocking the activity of mitogen activate protein kinase (MAPK) and the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK) family proteins. These kinases inhibit apoptosis and encourage proliferation. Four human NB cell lines were used to study the effects of Harmine treatment: SK-N-BE(2)-C and KELLY (MYCN amplified) as well as SK-N-AS and SK-N-FI (MYCN single copy). Molecular interaction models of Harmine bound to DYRK family kinases were generated by computational docking using x-ray structures. The anti-cancer properties of Harmine were analyzed by real-time cell viability assays, in a dose-dependent manner, over a 72 hour period. The IC50 values were 169.9, 170.8, and 791.7 μM for SK-N-BE(2)-C, KELLY, and SK-N-FI, respectively, after 72 hours. Apoptosis assays for caspase activation, PARP cleavage, and annexin V induction, were performed using Western blot and flow cytometry. NB cell line exposure to 100 μM Harmine resulted in caspase-3/7 and caspase 9 activation, PARP cleavage, and annexin V-positive stained cells as early as 24 hours after treatment, indicating apoptosis induction. These results led us to investigate the clinical correlations of DYRK family gene expression in NB tumors. The patient results support our hypothesis that Harmine induces NB cell death through a cellular mechanism that involves DYRK family kinases and triggers caspase-mediated apoptosis. Citation Format: Katie L. Uhl, Chad R. Schultz, Dirk Geerts, Andre S. Bachmann. Potential role of DYRK family kinases in harmine-induced apoptosis in 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 1902.
Abstract 1061: Advanced quantitative mass-spectrometry-based SILAC proteome profiling of Y-box binding protein-1 (YB-1) overexpressing breast cancer cells unravels proteins involved in metastasis
Authors: Jia Pei Lim, Sunitha Nair, Sukanya Shyamasundar, Jayantha Gunaratne, Boon Huat Bay
Journal: Cancer Research (2018)

Abstract Metastasis is responsible for the majority of cancer related deaths and remains a global medical challenge in cancer treatment. The Y-box binding protein-1 (YB-1), a DNA and RNA binding protein, is known to regulate a plethora of fundamental cellular processes, including cell proliferation, chemoresistance and DNA repair. There is also cumulative evidence that YB-1 enhances breast cancer spread although the exact mechanism of YB-1-mediated metastasis is still not clear. Hence, we aim to determine the role of YB-1 overexpression in breast cancer progression. We first stably overexpressed YB-1 in non-aggressive MCF7 breast cancer cells (MCF7-YB-1) using a turboGFP tagged plasmid and performed phenotypic assays. We observed a significant increase in cell migration in MCF7-YB-1 in the Boyden chamber migration assay, which was substantiated by performing live imaging of the cells in a wound healing assay. Furthermore, a significant decrease in cell proliferation with G1 phase arrest was observed by the alamarBlue assay and flow cytometry analysis of propidium iodide staining, respectively for MCF7-YB-1 cells. We then performed a whole proteome analysis by stable isotope labelling with amino acids in cell culture (SILAC), a powerful proteomics platform. The whole proteome analysis identified 122 upregulated proteins and 120 downregulated proteins in the MCF-7-YB-1 cells. Bioinformatics analysis of the differentially regulated proteins using the Metacore software revealed the involvement of proteins that promote cell migration and invasion, such as those belonging to the S100 family which are enriched in the extracellular vesicles and exosome compartment, providing some mechanistic insights into the metastasis promoting role of YB-1. Taken together, our results showed that YB-1 could enhance the migratory potential of breast cancer cells, an important step in the metastatic cascade and therefore warrants a more in-depth study. Acknowledgement: Jia Pei Lim is a recipient of Ong Hin Tiang Scholarship in Cancer Research. This research was supported by Ministry of Education Grant (MOE2013-T2-1-129). Citation Format: Jia Pei Lim, Sunitha Nair, Sukanya Shyamasundar, Jayantha Gunaratne, Boon Huat Bay. Advanced quantitative mass-spectrometry-based SILAC proteome profiling of Y-box binding protein-1 (YB-1) overexpressing breast cancer cells unravels proteins involved in metastasis [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 1061.
Usefulness of Pravastatin in Primary Prevention of Cardiovascular Events in Women
Authors: KyoichiMizuno, NoriakiNakaya, YasuoOhashi, NaokoTajima, ToshioKushiro, TamioTeramoto, ShinichiroUchiyama, HaruoNakamura
Journal: Circulation (2008)

Background— It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. Methods and Results— Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for ≥5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differe...
Abstract 4464: CPEB-2 is a tumor-suppressor gene in human breast cancer
Authors: Peeyush K. Lala, Joshua Tordjman, Mehdi Amiri, Asma Hasan, David Hess, Mousumi Majumder
Journal: Cancer Research (2018)

Abstract We found that expression of cyclooxygenase (COX)-2 promotes breast cancer progression by multiple mechanisms, including stimulation of cancer cell proliferation, migration, invasiveness, epithelial-to-mesenchymal transition (EMT), angiogenesis, lymphangiogenesis and induction of stem-like cells (SLC). Through combined gene expression and microRNA microarray analyses of COX-2-transfected MCF-7 cells, we identified two oncogenic miRNAs, miR-526b and miR-655, up-regulated by COX-2. They collectively target 13 tumour suppressor-like genes down-regulated by COX-2, of which Cytoplasmic Polyadenylation Element-Binding Protein -2 (CPEB-2) was the single common target, whose function is unclear in breast cancer. CPEB-2 is known to downregulate mesenchymal transcription factor TWIST1 and translation of HIF1α. CPEB-2 has multiple isoforms (A-F), of which a high B: A isoform ratio was reported to confer anoikis-resistance, a metastatic phenotype, in breast cancer cells. We found that CPEB-2 expression was inversely correlated with COX-2 or the microRNAs miR-526b and miR-655 in breast cancer cell lines; it was very high in a non-tumorigenic mammary epithelial cell line MCF10A.To define its functional roles we knocked out CPEB-2 in MCF10A cells by CRISPR/Cas9-double nickase approach. CPEB-2-KO cells exhibited oncogenic phenotypes in vitro: increased proliferation, migration, invasion, EMT phenotype (decreased E-Cadherin, increased Vimentin, N-cadherin, SNAI1, and ZEB1) and SLC properties (increased spheroid formation and SLC-linked markers). P53 protein was found to be a novel translationally- regulated target of CPEB-2. CPEB-2KO cells, but not wild-type cells, produced lung colonies upon intravenous injection and orthotopic tumors (identified by HLA staining) upon implantation at mammary sites in NOD/SCID/IL2Rϒ-null mice. In human breast cancer tissues, compared to non-tumour breast tissues, isoform A/E of CPEB2 revealed a lower expression in HER2+ breast cancer samples, suggesting that CPEB-2A/E are the tumour-suppressor isoforms. These findings demonstrate that CPEB-2 is a tumour suppressor gene in breast cancer. (Supported by the OICR and the NSERC) Citation Format: Peeyush K. Lala, Joshua Tordjman, Mehdi Amiri, Asma Hasan, David Hess, Mousumi Majumder. CPEB-2 is a tumor-suppressor gene in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4464.
Ubiquitin-Proteasome Pathway as a New Target for the Prevention of Restenosis
Authors: SilkeMeiners, MichaelLaule, WimRother, ChristophGuenther, InesPrauka, PeterMuschick, GertBaumann, Peter-MichaelKloetzel, KarlStangl
Journal: Circulation (2002)

Background— The ubiquitin-proteasome system is the major intracellular protein degradation pathway in eucaryotic cells. It regulates central mediators of proliferation, inflammation, and apoptosis that are fundamental pathomechanisms in the development of vascular restenosis. Methods and Results— Effects of proteasome inhibition on neointima formation were studied in a balloon injury model in the rat carotid artery. Local application of the proteasome inhibitor MG132 (1 mmol/L) resulted in significant inhibition of intimal hyperplasia, that is, by 74% (P=0.008). This effect was accompanied by decreased proliferation, reduced infiltration of macrophages, and prolonged apoptosis, as determined by immunohistochemical and TUNEL analyses. Functional effects of proteasome inhibition on proliferation, activation of nuclear factor kappa B, and apoptosis were further characterized in rat primary vascular smooth muscle cells. MG132 dose-dependently inhibited vascular smooth muscle cell proliferation with 50% inhibi...
Suicide and Physician-Assisted Death for Persons With Psychiatric Disorders
Authors: Scott Y. H. Kim, Yeates Conwell, Eric D. Caine
Journal: JAMA Psychiatry (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Transcriptional Activation of the Zinc Finger Transcription Factor BTEB2 Gene by Egr-1 Through Mitogen-Activated Protein Kinase Pathways in Vascular Smooth Muscle Cells
Authors: KeikoKawai-Kowase, MasahikoKurabayashi, YoichiHoshino, YoshioOhyama, RyozoNagai
Journal: Circulation Research (1999)

Abstract—We have recently demonstrated that a developmentally regulated zinc finger protein, basic transcription regulatory element binding protein 2 (BTEB2), is induced in neointimal smooth muscle in response to vascular injury. In this study, we investigated the molecular mechanisms regulating BTEB2 expression in vascular smooth muscle cells (SMCs) in vitro. BTEB2 mRNA expression is rapidly and persistently induced in SMCs by phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor. We have isolated and characterized the promoter region of the human BTEB2 gene to determine the regulatory network controlling expression of this gene in vascular SMCs. Functional studies on the BTEB2 promoter coupled to a luciferase reporter gene demonstrated activation of the promoter by PMA and basic fibroblast growth factor. Both characterization of DNA-protein complexes in vitro and site-specific mutation analysis of the BTEB2 promoter have defined a 9-bp sequence, 5′-CGCCCGCGC-3′, located at −25, as the...
Abstract 5560: PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers
Authors: Hui Qin Wang, Jinsheng Liang, Iain Mulford, Fiona Sharp, Swann Gaulis, Yan Chen, Gina Trabucco, David Quinn, Joseph D. Growney, Matthew J. Meyer, Juliet Williams, Peter Hammerman, Francesco Hofmann, Glenn Dranoff, Jeffrey Engelman, Jennifer Mataraza, Ensar Halilovic
Journal: Cancer Research (2018)

Abstract p53 is a transcription factor that plays a central role in guarding genomic stability of the cell through cell cycle arrest or induction of apoptosis. It has also been reported that p53 participates in the regulation of tumor immunity and in homeostatic regulation of immune responses. However, the immunomodulatory effect of p53 in tumor and the tumor microenvironment is not well understood. From gene expression and immunohistochemical analysis of pre- and post-treatment biopsies from patients treated with the MDM2 inhibitor NVP-CGM097, we observed upregulation of immune checkpoint transcripts (PD1 and PDL1), and an increase in the number of CD8+ tumor infiltrating lymphocytes. To investigate the immunomodulatory effect of p53 in more detail, we studied murine syngeneic models treated with NVP-HDM201, a potent and selective second generation MDM2 inhibitor. We performed multi-color FACS analysis on tumors and tumor draining lymph nodes. With NVP-HDM201 treatment, we observed increase in numbers of CD103+ DC cells, capable of antigen cross-presentation. Furthermore, NVP-HDM201 increased the percentage of Tbet+EOMES-T cells in tumors as well as tumor draining lymph nodes and also resulted in increased ratios of CD8+ Tcells/Treg in tumor. In addition, levels of both PD-L1 on CD45- cells and PD-1 on CD4+ T cells were increased. Importantly, PD-1 and PD-L1 blockade enhanced HDM201 activity in p53 WT syngeneic mouse models but not in p53 mutated models. The rate of complete tumor regressions (CR) was significantly increased with combination treatment as compared to either treatment alone. The animals that achieved complete regressions also developed long lasting anti-tumor memory against the specific tumor cells as evidenced by re-challenge experiments. Taken together, these results demonstrate that MDM2 inhibition triggered adaptive immunity which was further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in cancer patients with wildtype p53. Citation Format: Hui Qin Wang, Jinsheng Liang, Iain Mulford, Fiona Sharp, Swann Gaulis, Yan Chen, Gina Trabucco, David Quinn, Joseph D. Growney, Matthew J. Meyer, Juliet Williams, Peter Hammerman, Francesco Hofmann, Glenn Dranoff, Jeffrey Engelman, Jennifer Mataraza, Ensar Halilovic. PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers [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 5560.
Selective Downregulation of VEGF-A165, VEGF-R1, and Decreased Capillary Density in Patients With Dilative but Not Ischemic Cardiomyopathy
Authors: DietmarAbraham, ReinholdHofbauer, RomanaSchäfer, RolandBlumer, PatrickPaulus, AureliaMiksovsky, HannesTraxler, AlfredKocher, SeyedhosseinAharinejad
Journal: Circulation Research (2000)

Abstract—Cardiomyopathy (CM) comprises a heterogeneous group of diseases, including ischemic (ICM) and dilative (DCM) forms. The pathogenesis of primary DCM is not clearly understood. Recent studies in mice show that vascular endothelial growth factor (VEGF) is involved in ICM. Whether VEGF plays a role in human CM is unknown. We examined the mRNA and protein expression of VEGF and its receptors in hearts of patients with end-stage DCM and ICM and in healthy individuals using real-time polymerase chain reaction and Western blotting. Number of capillaries, area of myocytes, and collagen were calculated in cardiac biopsies using transmission electron microscopy. In DCM, except for VEGF-C, mRNA transcript levels of VEGF-A165, VEGF-A189, and VEGF-B and the protein level of VEGF-A and VEGF-R1 were downregulated compared with controls (P<0.05). However, in ICM, mRNA transcript levels of VEGF isoforms and protein levels of VEGF-C were upregulated. The vascular density was decreased in DCM but increased in ICM co...
Calcineurin Plays a Critical Role in Pressure Overload–Induced Cardiac Hypertrophy
Authors: MasakiShimoyama, DoubunHayashi, EikiTakimoto, YunzengZou, ToruOka, HirokiUozumi, SumiyoKudoh, FutoshiShibasaki, YoshioYazaki, RyozoNagai, IsseiKomuro
Journal: Circulation (1999)

Background—Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload–induced cardiac hypertrophy. Methods and Results—Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload–induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. Conclusions—The present results suggest that the calcineuri...
Abstract 1661: Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-<i>d</i>]pyrimidin-7-one
Authors: Zhixing Wu, Boqiao Fu, Changjiang Qiao, Ashila Nagaraju, Dai Lu
Journal: Cancer Research (2018)

Abstract Tyrosine kinases regulate cell proliferation, survival, invasion and angiogenesis during tumor initiation and progression. The Abelson (ABL) family of protein kinases comprises ABL1 and ABL2, which link diverse extracellular stimuli to signaling pathways that control cell growth, survival, invasion, adhesion and migration. Inhibition of ABLs has been implied in many type of hematopoietic malignancies and solid tumors. The compound PD173955 is a potent ABL kinase inhibitor. It was developed from the scaffold pyrido[2,3-d]pyrimidin-7-one by Parke-Davis (Pfizer). To discover novel ABL inhibitors, we investigated the scaffold pyrano[2,3-d]pyrimidin-7-one, which is structurally analogous to pyrido[2,3-d]pyrimidin-7-one. This novel scaffold has not been extensively studied in synthetic chemistry and pharmacology. The compound LDK1504 generated from this scaffold is a close analog of PD173955. It was synthesized as a prototypical compound from the pyrano[2,3-d]pyrimidin-7-one scaffold. In the enzymatic assays, LDK1504 was demonstrated with an inhibitory activity comparable to PD173955 for ABL1 kinase. It can inhibit the ABL1 kinase with an IC50 of 18.7 nM. Further optimization leads to the identification of LDK1512 (Kd = 0.38 nM; IC50 = 1.27 nM) against ABL1. The preparation of this class of compounds was achieved through a facile synthesis of 6-bromo-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one followed by Suzuki coupling reaction and derivatization of the C-2 position of the pyrimidine ring. In this presentation, our synthesis, preliminary SAR of this class of compounds, and kinase selectivity profiling will be discussed. Citation Format: Zhixing Wu, Boqiao Fu, Changjiang Qiao, Ashila Nagaraju, Dai Lu. Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-d]pyrimidin-7-one [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 1661.
Detection of Internal Thoracic Artery Dissection at Coronary Anastomosis Using Intraoperative 15-MHz High-Frequency Epicardial Ultrasound
Authors: TaijuWatanabe, HirokuniArai, KeijiOi, TsuyoshiHachimaru, HidehitoKuroki, TatsukiFujiwara, TomohiroMizuno
Journal: Circulation (2014)