tbuckley/cabot-search huggingface dataset:
Abstract 3941: Heparan sulfate, a new target for platinum in metastatic TNBC
Authors: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell
Journal: Cancer Research (2018)

Abstract Heparan sulfate (HS) are linear polysaccharides conjugated to proteins, heparan sulfate proteoglycans (HSPGs), located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation. These sulfate clusters mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding. The biological consequences of PPCs metalloshielding HS will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis. High heparanase expression correlates with increased metastatic potential and poor clinical prognosis. PPC-HS interactions inhibit cleavage of a model pentasaccharide by heparanase and further modulated bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models. Further, we examine the anti-metastatic and anti-angiogenic effects of PPC-HS metalloshielding in these in vivo models through multiple growth factor signaling pathways (bFGF, HB-EGF, VEGF), and heparanase activity in breast cancer and endothelial cells. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting. Chicago 14-17 April 2018 Citation Format: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell. Heparan sulfate, a new target for platinum in metastatic TNBC [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 3941.
Abstract 5829: CDK8 inhibitor SEL120-34A targets CD34 positive AML cells by regulation of various transcriptional programs involved in maintenance of leukemia stem cells
Authors: Eliza Majewska, Milena Mazan, Michal Mikula, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Malgorzata Statkiewicz, Urszula Kuklinska, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Michal Combik, Jerzy Ostrowski, Krzysztof Brzozka, Tomasz Rzymski
Journal: Cancer Research (2018)

Abstract Despite heterogeneity deregulated transcription is one of the universal features of leukemia cells. This has paved the way for the development of active compounds targeting epigenetic and transcriptional factors. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. In many cancer cells SEL120-34A regulates expression of STAT1- dependent genes as a major transcriptional effect. In AML cells regulation of NUP98-HOXA9 - dependent transcription and other transcriptional programs involved in maintenance of leukemia stem cells have been observed as a dominant mechanism of action. Treatment with the compound resulted in a differential efficacy on CD34 positive AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. Prolonged exposure of AML cells lines to chemotherapy led to the enrichment in population of resistant CD34 positive cells, which proved to be oversensitive to SEL120-34A treatment, providing rationale for rational combinations with approved drugs. Further clinical development of SEL120-34A is warranted as a novel therapeutic approach in relapsed and refractory AML. Citation Format: Eliza Majewska, Milena Mazan, Michal Mikula, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Malgorzata Statkiewicz, Urszula Kuklinska, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Michal Combik, Jerzy Ostrowski, Krzysztof Brzozka, Tomasz Rzymski. CDK8 inhibitor SEL120-34A targets CD34 positive AML cells by regulation of various transcriptional programs involved in maintenance of leukemia stem 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 5829.
Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age
Authors: StephanGielen, MarcusSandri, IrinaKozarez, JürgenKratzsch, DanielTeupser, JoachimThiery, SandraErbs, NormanMangner, KarstenLenk, RainerHambrecht, GerhardSchuler, VolkerAdams
Journal: Circulation (2012)

Background—Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. Methods and Results—Sixty CHF patients (30 patients aged ≤55 years, mean age 46±5 years; 30 patients aged ≥65 years, mean age 72±5 years) and 60 healthy controls (30 subjects aged ≤55 years, mean age 50±5 years; 30 subjects aged ≥65 years, mean age 72±4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained....
Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma
Authors: Antoine L’Hermitte, Sandrine Pham, Mathilde Cadoux, Gabrielle Couchy, Stefano Caruso, Marie Anson, Anne‐Marie Crain‐Denoyelle, Séverine Celton‐Morizur, Satoshi Yamagoe, Jessica Zucman‐Rossi, Chantal Desdouets, Jean‐Pierre Couty
Journal: Hepatology (2018)

Leukocyte cell‐derived chemotaxin‐2 (LECT2) was originally identified as a hepatocyte‐secreted chemokine‐like factor and a positive target of β‐catenin signaling. Here, we dissected out the mechanisms by which LECT2 modulates hepatocellular carcinoma (HCC) development using both HCC mouse models and human HCC samples. We have demonstrated that LECT2 exhibits dual abilities as it has profound repercussions on the tumor phenotype itself and the immune microenvironment. Its absence confers Ctnnb‐1‐mutated tumor hepatocytes a stronger ability to undergo epithelial to mesenchymal transition and fosters the accumulation of pejorative inflammatory monocytes harboring immunosuppressive properties and strong tumor‐promoting potential. Consistent with our HCC mouse model, a low level of LECT2 in human HCC is strongly associated with high tumor grade and the presence of inflammatory infiltrates, emphasizing the clinical value of LECT2 in human liver tumorigenesis. Conclusion: Our findings have demonstrated that LECT2 is a key player in liver tumorigenesis because its absence reshapes the tumor microenvironment and the tumor phenotype, revealing LECT2 as a promising immunotherapeutic option for HCC.
Plasma MicroRNA Profiling Reveals Loss of Endothelial MiR-126 and Other MicroRNAs in Type 2 Diabetes
Authors: AnnaZampetaki, StefanKiechl, IgnatDrozdov, PeterWilleit, UrsulaMayr, MariannaProkopi, AgnesMayr, SiegfriedWeger, FriedrichOberhollenzer, EnzoBonora, AjayShah, JohannWilleit, ManuelMayr
Journal: Circulation Research (2010)

Rationale:MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications. Objective:In this study, we explore plasma miRNA profiles in patients with DM. Methods and Results:Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in ...
Abstract 1846: HPV oncoproteins cause specific types of chromosomal instability in head and neck cancer
Authors: Laura C. Funk, Denis L. Lee, Randall J. Kimple, Paul F. Lambert, Beth A. Weaver
Journal: Cancer Research (2018)

Abstract Aneuploidy, a karyotype that differs from a multiple of the haploid, is a hallmark of cancer. Aneuploidy can be caused by an ongoing rate of chromosome missegregation during mitosis, known as whole chromosomal instability (CIN). Work from our lab and others has shown that while low rates of CIN can promote tumorigenesis, high levels of CIN are tumor suppressive. Combining two insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We recently showed that the chemotherapy drug paclitaxel causes CIN due to multipolar divisions in breast cancer. Preliminary evidence suggests that tumors which exhibit CIN prior to therapy are sensitized to paclitaxel because it increases their level of CIN over a maximally tolerated threshold. Radiation also induces CIN, and rectal adenocarcinomas which exhibit CIN prior to treatment are sensitized to chemoradiation therapy. Human papillomavirus (HPV), specifically HPV subtype 16, is a growing cause of head and neck cancer worldwide. In cervical cancer, HPV is associated with CIN, which has been attributed largely to the expression of its E6 and E7 oncoproteins. HPV+ head and neck cancer patients show improved responses to radiation therapy than HPV- head and neck patients, potentially due to an increased basal rate of CIN. Here, we tested the ability of HPV E6, E7, or E6+E7 expression to induce CIN in normal oral keratinocytes (NOKs). Expression of E6 alone robustly induced misaligned chromosomes and multipolar spindles with supernumerary centrosomes, while E7 expression alone produced more moderate effects. Combined expression of E6 and E7 exacerbated the phenotypes observed in NOKs expressing E6 alone. Expression of E6, either alone or in combination with E7 caused reduced protein levels of the mitotic kinesin CENP-E, which is sufficient to induce misaligned chromosomes. Interestingly, HPV+ patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma showed less evidence of mitotic defects than NOKs expressing E6 alone. A subset of HPV+ PDX tumors showed an increase in misaligned chromosomes when compared to HPV- tumors, but no increase in lagging chromosomes or multipolar spindles was observed. Together, these data suggest HPV infection causes an incompletely penetrant increase in specific types of CIN in head and neck cancer and that a basal rate of CIN may be predictive of treatment response independent of HPV status. Citation Format: Laura C. Funk, Denis L. Lee, Randall J. Kimple, Paul F. Lambert, Beth A. Weaver. HPV oncoproteins cause specific types of chromosomal instability in head and neck 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 1846.
Abstract 20391: Fluid Overload in Children Hospitalized With Heart Failure: How Common and How Much?
Authors: John C Dykes, Jenna F Kruger, Beth D Kaufman, Esther Liu, Katelin M Dennis, Alaina K Kipps, Vamsi V Yarlagadda, Sharon Chen, Seth A Hollander, David N Rosenthal, Christopher S Almond
Journal: Circulation (2016)

Background: Studies suggest it is uncommon for children hospitalized with acute decompensated heart failure (ADHF) to present with overt signs of fluid overload (FO). It is unclear whether children...
Effect of Exercise Training on Myocardial Remodeling in Patients With Reduced Left Ventricular Function After Myocardial Infarction
Authors: PaulDubach, JonathanMyers, GeraldDziekan, UteGoebbels, WalterReinhart, PaulVogt, RetoRatti, PeterMuller, RistoMiettunen, PeterBuser
Journal: Circulation (1997)

Background There are conflicting reports on the effects of training on the remodeling process in post–myocardial infarction patients with ventricular damage. Methods and Results Twenty-five patients with reduced ventricular function (mean ejection fraction, 32.3±6%) after an anteroseptal or inferolateral myocardial infarction were randomized to an exercise group (n=12) or a control group (n=13). Patients in the exercise group resided in a rehabilitation center for 2 months and underwent a training program consisting of two 1-hour sessions of walking daily, along with four monitored 45-minute sessions of stationary cycling weekly. Before and after the study period, maximal exercise testing and cardiac MRI were performed. Oxygen uptake increased 26% at maximal exercise (19.7±3 to 23.9±5, P<.05) and 39% at the lactate threshold (P<.01) in the exercise group, whereas control values did not change. No differences were observed within or between groups in MRI measures of end-diastolic (187±47 pre versus 196±35 ...
Abstract 3050: Imaging tissue extracellular pH for the differential diagnosis of coccidioidomycosis and lung cancer
Authors: Leila Renee Lindeman, Edward A. Randtke, Lisa F. Shubitz, Christine M. Howison, Kyle M. Jones, Mark D. Pagel
Journal: Cancer Research (2018)

Abstract Introduction: Our objective was to determine whether acidoCEST MRI—a novel, non-invasive MRI method that measures extracellular pH (pHe)—can differentiate between lung tumors and coccidioidomycosis (valley fever) granulomas within in vivo mouse models of lung cancer and valley fever. Methods: To develop a spontaneous murine lung tumor model, A/J mice received orthotopic injections of urethane to induce formation of lung adenocarcinomas. The Valley Fever Center for Excellence at the University of Arizona infected SW mice with a BSL 2-compatible mutant Coccidioides strain, Δcps1, to develop our preclinical valley fever model. All scans were performed with a Bruker BioSpin 7T MRI system. For all MRI scans, mice were anesthetized with 2.0% isofluorane, respiration and body temperature were monitoreduring scans, and body temperature was maintained at 37 °C. Respiration-triggering (gating) was used in all imaging sequences to compensate for motion artifacts in the lung. For optimal gating, the mouse's respiration rate was maintained at &amp;lt; 50 breaths per minute. Each mouse was scanned with acidoCEST MRI using 370 mg/mL Iopamidol (200 μL IV bolus, 400 μL/hr IV infusion). AcidoCEST MRI (3.5 μT, 300 ms imaging time, 6000 ms presaturation pulse) was performed according to previously published methods, updated with improved respiration gating. For acidoCEST MRI, the saturation pulse continued until terminated by the gating trigger. Spatial pHe maps of tumor and granuloma ROI were produced using Bloch fitting in Matlab 2014a. Average lesion pHe and iopamidol concentration we also recorded. Results: AcidoCEST MRI was successfully applied to the in vivo imaging of murine lung tumors and coccidioidomycosis granulomas. Lung tumors demonstrated successful uptake of the iopamidol contrast agent, with an average concentration of approximately 40 mM. pHe values in the tumor ROI ranged from 6.5 to 7.2 with an average value of 6.64. Granulomas demonstrated successful uptake of iopamidol with an average concentration of about 75 mM. pHe values in granulomas ranged from 7.2 to 7.4 with an average value of 7.29. Conclusion: AcidoCEST MRI may be used to quantify the pHe of murine lung tumors and coccidioidomycosis granulomas in vivo. Our results show that pHe is a promising biomarker for the differential diagnosis of coccidioidomycosis and lung cancer. Citation Format: Leila Renee Lindeman, Edward A. Randtke, Lisa F. Shubitz, Christine M. Howison, Kyle M. Jones, Mark D. Pagel. Imaging tissue extracellular pH for the differential diagnosis of coccidioidomycosis and lung 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 3050.
Association of Maternal Insecticide Levels With Autism in Offspring From a National Birth Cohort
Authors: Alan S. Brown, Keely Cheslack-Postava, Panu Rantakokko, Hannu Kiviranta, Susanna Hinkka-Yli-Salomäki, Ian W. McKeague, Heljä-Marja Surcel, Andre Sourander
Journal: American Journal of Psychiatry (2018)

Objective: Autism is a complex neurodevelopmental disorder with a largely unknown etiology. To date, few studies have investigated prenatal exposure to toxins and risk of autism by using maternal biomarkers of exposure. Persistent organic pollutants are lipophilic halogenated organic compounds and include the insecticide dichlorodiphenyltrichloroethane (DDT), as well as its metabolite p,p′-dichlorodiphenyl dichloroethylene (p,p′-DDE), and polychlorinated biphenyls (PCBs). The objective of this study was to test whether elevated maternal levels of persistent organic pollutants are associated with autism among offspring. Method: The investigation was derived from the Finnish Prenatal Study of Autism, a national birth cohort study based on a nested case-control design. Cases of autism among children born between 1987 and 2005 were ascertained by national registry linkages. In cases of childhood autism and matched control subjects (778 matched case-control pairs), maternal serum specimens from early pregnancy were assayed for levels of p,p′-DDE and total levels of PCBs. Results: The odds of autism among offspring were significantly increased with maternal p,p′-DDE levels that were in the highest 75th percentile, with adjustment for maternal age, parity, and history of psychiatric disorders (odds ratio=1.32, 95% CI=1.02, 1.71). The odds of autism with intellectual disability were increased by greater than twofold with maternal p,p′-DDE levels above this threshold (odds ratio=2.21, 95% CI=1.32, 3.69). There was no association between total levels of maternal PCBs and autism. Conclusions: These findings provide the first biomarker-based evidence that maternal exposure to insecticides is associated with autism among offspring. Although further research is necessary to replicate this finding, this study has implications for the prevention of autism and may provide a better understanding of its pathogenesis.
Abstract 817: Overcoming FGFRs-mediated drug resistance by inhibiting myristoylation of FRS2α
Authors: Houjian Cai, Qianjin Li
Journal: Cancer Research (2018)

Abstract Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling facilitates tumor initiation and progression. Although there are currently approved inhibitors and agents in clinical trials targeting FGFR kinase activity that show therapeutic benefit, over-expression and/or mutations of FGFRs eventually confer drug-resistance and bypass the mechanisms of kinase inhibitors in a variety of cancer types. We hypothesize that a compound blocks the myristoylation of FRS2α, thus suppressing its interaction with FGFRs or FGFRs drug resistant mutants (FGFRsDRM) and downstream proteins. As a result, it inhibits oncogenic signaling and tumor progression mediated by FGF/FGFRs or FGFRsDRM. The goal of this study is to investigate if the novel lead compound inhibits FGF/FGFRs oncogenic signaling and overcomes FGFRsDRM mediated drug resistance. We used CRISPR/Cas9 mediated gene knockout to demonstrate that FRS2α is essential for FGF/FGFR signaling. The myristoylation of FRS2α was detected by Click chemistry. Additionally, inhibition of cell proliferation, migration, invasion assays and cell cycle analysis were analyzed in numerous cancer cells. Prostate regeneration assay and xenograft tumor models were applied for in vivo studies. We demonstrate that loss of myristoylation of FRS2α, a scaffold protein key in FGFRs signaling, inhibits FGF/FGFRs-mediated oncogenic signaling and FGF10-induced tumorigenesis. Additionally, a previously synthesized myristoyl-CoA analog, B13, which targets the activity of N-myristoyltransferases, suppresses FRS2α myristoylation, and modulates the phosphorylation and localization of FRS2α at the cytoplasmic membrane. B13 exhibited an inhibitory effect on oncogenic signaling induced by wild type FGFRs and their drug resistant mutants (FGFRsDRM). The single agent or in collaboration with an FGFR inhibitor suppressed FGF induced wild type FGFR or FGFRDRM initiated PI3K and/or MAPK signaling, subsequently inhibiting cell proliferation and migration in a variety of cancer cell types by inducing cell cycle arrest. Finally, B13 significantly inhibited growth of xenograft tumors without pathological toxicity to the liver, kidney, or lung in vivo. Our study demonstrates that B13, a myristoyl-CoA analog, inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. This study provides a novel therapeutic approach for inhibiting cancer progression mediated by FGF/FGFRs and their drug resistant mutants. Citation Format: Houjian Cai, Qianjin Li. Overcoming FGFRs-mediated drug resistance by inhibiting myristoylation of FRS2α [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 817.
Pathogenesis of Dissecting Aneurysm
Journal: JAMA (1963)

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服用环氧化酶-2抑制剂或传统非甾体类抗炎药的患者发生心肌梗死的风险：人群巢式病例对照研究
Authors: Julia, Hippisley-Cox, Carol, Coupland, 朱丽琳（译）
Journal: BMJ (2005)

目的：比较2000年至2004年间初级卫生保健中服用环氧化酶-2和其他非甾体类抗炎药（NSAIDs）的患者中发生心肌梗死的相对风险；确定既往有或无冠心病的患者，以及服用或未服用阿司匹林的患者发生这种风险的程度。