tbuckley/cabot-search huggingface dataset:
Abstract 26: Myocardial Phosphodiesterase-2A Is Upregulated in Human and Experimental Heart Failure and Blunts Cardiac β-Adrenergic Inotropic Responsiveness
Authors: Christiane Vettel, Hind Mehel, Julius Emons, Katrin Wittkoepper, Danilo Seppelt, Susanne Lutz, Viacheslav O Nikolaev, Samuel Sosalla, Wolfram H Zimmermann, Grégoire Vandecasteele, Rodolphe Fischmeister, Ali El-Armouche
Journal: Circulation Research (2012)

Augmented cGMP- and diminished cAMP-signaling within cardiomyocytes is characteristic for failing hearts. Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of cyclic-nucleotide hydrolyzing enzymes, controlling cAMP and cGMP levels. Among them the PDE-2A isoform has the unique property to be stimulated by cGMP but primarily hydrolyzing cAMP. This appears to mediate a negative cross-talk between both signaling pathways. However, a potential role for PDE-2A in the failing heart has not been addressed yet. Here we show that PDE-2A protein levels were ∼2-fold higher in failing human hearts as well as in a large animal heart failure model from dog hearts subjected to rapid-pacing (n≥6, p&lt;0.05). Intriguingly, PDE-2A protein levels were normal in hypertrophied hearts from patients with preserved cardiac function who underwent aortic valve replacement. Chronic beta-adrenergic stimulation by catecholamine infusions enhanced cAMP hydrolyzing activity of PDE-2A by four-fold (n≥6, p&lt;0.05) in rat hearts in vivo and in isolated cardiomyocytes (measured by radioimmunoassay and FRET-based sensors, respectively) and correlated with blunted beta-adrenergic responsiveness. Consistent with this observation, overexpressed PDE-2A, which localized to the sarcomeric Z-line, blunted the rise in cAMP by 70% (n≥6, p&lt;0.05) and abolished the positive inotropic effect after acute beta-adrenergic stimulation by 70% (n≥6, p&lt;0.05) in isolated cardiomyocytes. Notably, those cardiomyocytes also showed marked protection from norepinephrine-induced hypertrophic responses, e. g. 40% less increase in cell surface area (n≥10, p&lt;0.05). In summary, PDE-2A is markedly upregulated in human and experimental failing hearts. This may constitute an important defense mechanism during cardiac stress, by antagonizing the cAMP-mediated toxic effects. Thus, activating myocardial PDE-2A may represent a new intracellular anti-adrenergic therapeutic strategy in heart failure.
Fenretinide (4-HPR)/Lym-X-Sorb (LXS) oral powder plus ketoconazole in patients with high-risk (HR) recurrent or resistant neuroblastoma: A New Approach to Neuroblastoma Therapy (NANT) Consortium trial.
Authors: Barry James Maurer, Julia Lynne Glade Bender, Min Hee Kang, Judith Villablanca, Denice Wei, Susan G. Groshen, Shengping Yang, Scarlett Czarnecki, Meaghan P. Granger, Howard M. Katzenstein, Brian D. Weiss, Katherine K. Matthay, C. Patrick Reynolds, Araz Marachelian
Journal: Journal of Clinical Oncology (2014)

10071 Background: Fenretinide (4-HPR), a cytotoxic retinoid with preclinical activity in neuroblastoma (NB), formulated as 4-HPR/LXS oral powder increased plasma levels over a capsule formulation but exhibited a PK plateau at higher doses (Pediatr Blood Cancer 60:1801, 2013). Two expansion cohorts were undertaken to assess effects on 4-HPR plasma levels of: 1) removing dietary restrictions, 2) adding ketoconazole, an inhibitor of 4-HPR metabolism. Methods: Eligible patients had high-risk NB with recurrent or refractory disease, including in complete response (CR) after relapse (Cohort One-only). Treatment in Cohort One was 4-HPR at 1500 mg/m2/day, divided TID, given on Days 1-7, every 3 weeks, with an unrestricted diet. In Cohort Two, concurrent oral ketoconazole (6 mg/kg/day) was given on Days 1-7. Results: Cohort One accrued 23 patients (3 not treated) with 15 eligible for PK analysis; Cohort Two accrued 22 patients, with 16 eligible for PK analysis (3 too early). There were no Course 1 DLT’s. Grade 3 toxicities included rash, elevated triglycerides, lymphopenia, diarrhea, and transient transaminase elevation. Overall, patients received a median of 3 (range: <1-27) courses. In Courses 1 and 2, the mean (95% confidence interval) Day 7, 4-HPR peak plasma level (µM) at 4-6 hours post-morning dose for Cohort One was 11.7 (8.3, 15.1) and for Cohort 2 was 18.4 (14.6, 22.1). Ketoconazole significantly increased peak 4-HPR plasma levels (p=0.005, mixed effects ANOVA). Of 16 patients in Cohort One and 18 patients in Cohort Two with evaluable disease at study entry, there were 2 complete responses, 1 partial response, 1 mixed response (MIBG CR), 14 stable disease, and 12 progressive disease; 4 patients did not complete 1st course. For the 34 patients with evaluable disease, the median progression-free survival (PFS) is 4.1 (1.35-36.9+) months. Conclusions: 4-HPR/LXS + ketoconazole was tolerated and increased 4-HPR plasma levels. Objective responses and encouraging PFS in this heavily pre-treated patient population support evaluation of 4-HPR/LXS with ketoconazole in future trials of high-risk neuroblastoma. Clinical trial information: NCT00295919.
Abstract 2111: Ciclopirox inhibits tumor cell motility by suppressing protein expression of small GTPases and phosphorylation of paxillin
Authors: Shile Huang, Tao Shen
Journal: Cancer Research (2017)

Abstract Ciclopirox olamine (CPX), an off-patent antifungal drug, is used for the treatment of superficial mycoses. Recent studies have demonstrated that CPX also possesses potent anticancer activity by inhibiting cell proliferation and inducing cell death in tumor cells. However, it is unknown whether CPX inhibits cell motility. In the present study, we found that CPX potently inhibited cell motility in a concentration-dependent manner in rhabdomyosarcoma (Rh30 and RD) cells, which was independent of the reduction of cell viability. As small GTPases (RhoA, Cdc42, and Rac1) and focal adhesion proteins (paxillin) play critical roles in the regulation of cell motility, we further studied whether CPX affects these proteins. Our Western blot analysis revealed that CPX did inhibit cellular protein expression of RhoA, Cdc42 and Rac1. However, by RT-PCR analysis, CPX did not alter the mRNA levels of the small GTPases. As microRNAs (miRNAs) can regulate protein expression at transcriptional and post-transcriptional levels, we investigated the effect of CPX on the expression of miRNAs. Our miRNA PCR array revealed that treatment with 10 μM of CPX for 24 hours upregulated the expression of 27 miRNAs by 2.04-6.10 fold, and downregulated the expression of 7 miRNAs by 2.00-7.89 fold in Rh30 cells. Further research is ongoing to identify whether these up/downregulated miRNAs are linked to the reduced expression of small GTPases and potentially more proteins. In addition, we found that CPX inhibited the phosphorylation of paxillin, despite no effect on the total cellular protein expression. The results suggest that CPX inhibits tumor cell motility at least by suppressing the protein expression of small GTPases and the phosphorylation of paxillin. Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA. Citation Format: Shile Huang, Tao Shen. Ciclopirox inhibits tumor cell motility by suppressing protein expression of small GTPases and phosphorylation of paxillin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2111. doi:10.1158/1538-7445.AM2017-2111
Abstract 868: GRK5 promotes a mesenchymal transition in prostate cancer
Authors: Joseph B. Black, Iqbal Mahmud, Hamsa Thayele Purayil, Yehia Daaka
Journal: Cancer Research (2017)

Abstract Locally advanced and metastatic prostate cancer is incurable, despite decades of research targeting the activity of the androgen receptor (AR). Our lab previously identified G protein-coupled receptor 5 (GRK5) for its ability to regulate PCa progression, independent of AR activity. GRK5 partially partitions to the nucleus, wherein it has been shown to regulate the transcriptome in non-PCa models. To globally elucidate the mechanistic impact of GRK5 on PCa progression, we are investigating the impact of GRK5 on the PCa transcriptome. We hypothesize that GRK5’s regulation of the PCa transcriptome promotes tumor progression. To assay the effect of GRK5 on the PCa transcriptome, RNA sequencing was performed in two cell lines: PC3 Control (PC3 shGFP) and PC3 GRK5 Knockdown (PC3 shGRK5). Ontologic analysis identified the epithelial–mesenchymal transition (EMT) as being affected when GRK5 is depleted. The epithelial–mesenchymal transition (EMT) is highly associated with promoting PCa progression and chemoresistance, thus we selected this pathway for further investigation. Confirmatory western blot analysis and quantitative PCR (qPCR) validated that depleting GRK5 suppresses the expression of the mesenchymal markers Vimentin and N-Cadherin. Similarly, overexpression of GRK5 increases the expression of these mesenchymal markers. Stable overexpression of GRK5 promotes cells to develop a spindle-like morphology, indicative of a mesenchymal state. GRK5 mediates this mesenchymal transition through increasing the expression of the EMT transcription factor, Twist1. Further analysis identifies that GRK5 activity promotes in vitro invasion. Cell lines overexpressing GRK5 demonstrate an increase in resistance to docetaxel, the mainstay chemotherapy for advanced PCa. Overexpression of mutated forms of GRK5 that are relegated to the nucleus are able recapitulated all aforesaid changes, arguing that the nuclear activity of GRK5 mediates this effect. Collectively, this data presents a novel mechanism promoting PCa progression, independent of AR activity. Future work seeks to assay the ability of GRK5 to promote metastasis in vivo in mouse models. Note: This abstract was not presented at the meeting. Citation Format: Joseph B. Black, Iqbal Mahmud, Hamsa Thayele Purayil, Yehia Daaka. GRK5 promotes a mesenchymal transition in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 868. doi:10.1158/1538-7445.AM2017-868
Abstract 2390: Clinical validation of an epigenetic field of susceptibility to detect significant prostate cancer from 2 non-tumor biopsies
Authors: Bing Yang, Johnathon McCormick, Adam Schultz, Glen Leverson, Geoffrey Sonn, Cristina Magi-Galluzi, Eric A. Klein, Michael Fumo, David F. Jarrard
Journal: Cancer Research (2017)

Abstract Background: An epigenetic field of cancer susceptibility exists for prostate cancer that gives rise to multifocal disease in the peripheral zone. In a previous studies (Neoplasia 2013, J Urol 2014) we identified using methylation arrays over 50 altered regions in normal prostate tissue of men with prostate cancer. In the current multicenter study, a validation was performed to determine the predictive strength of this approach. Methods: We evaluated 2 archived, cancer negative prostate biopsy core tissue from 129 subjects from 4 urological centers. All negative cases (controls) underwent 2 or more repeat negative biopsies within 24 mo with a central review of all histopathology. Cancer cases were negative biopsies selected from patients who ultimately went prostate removal to confirm a final grade &amp;gt;Gleason Score 7. Biopsies were analyzed using pyrosequencing for DNA methylation changes at multiple CpGs surrounding the genes EVX1, CAV1, PLA2G16, FGF1, SPAG4 and NCR2. Analyses used multiplex logistic regression modeling with backward elimination. Results: Patients diagnosed with GS&amp;gt;7 cancer (77) and the control group (52) were similarly matched except for PSA (7 vs 5.8; p&amp;lt;0.03) and prostate size (46 vs 36; p&amp;lt;0.02). We observed robust methylation differences for all genes (p&amp;lt;0.05) (Table). A multiplex regression model for biomarker performance incorporating a gene combination of EVX1, NCR2, PLAG2 and SPAG4 discriminated non-tumor from tumor-associated tissues (AUC 0.744, p&amp;lt;0.0001). A multiplex model incorporating 3 genes (EVX1, PLA2G16, NCR2) and clinical information (PSA, age) identified patients with GS&amp;gt;7 prostate cancers (AUC 0.808, p=0.001). Conclusions: A widespread epigenetic field defect can be used to detect GS&amp;gt;7 prostate cancers in patients with histologically negative biopsies. This assay is sensitive in requiring only 2 biopsies and detects alterations in nontumor cells at distance from the cancer. This has the potential to decrease the need for repeat prostate biopsies, a procedure associated with cost and complications. Support: UW Ignitor; Gen X foundation Citation Format: Bing Yang, Johnathon McCormick, Adam Schultz, Glen Leverson, Geoffrey Sonn, Cristina Magi-Galluzi, Eric A. Klein, Michael Fumo, David F. Jarrard. Clinical validation of an epigenetic field of susceptibility to detect significant prostate cancer from 2 non-tumor biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2390. doi:10.1158/1538-7445.AM2017-2390
Abstract 1651: Targeting phosphatidylserine in combination with adoptive T cell transfer eliminates advanced tumors without off-target toxicities in a melanoma preclinical model
Authors: Daniel Hirschhorn-Cymerman, Sara Sara Schad, Sadna Budhu, Zhong Hong, Xia Yang, Hutchins T. Jeff, Bruce D. Freimark, Michael J. Gray, Jedd Wolchok, Taha Merghoub
Journal: Cancer Research (2017)

Abstract A viable strategy to treat advanced cancers includes transferring of tumor-specific T cells. T cells that recognize tumor antigens can be expanded and reinvigorated ex-vivo. Furthermore, autologous T cells can be genetically modified to express anti-tumor T cell receptors or chimeric antigen receptors. Although the potency and specificity of tumor-specific T cells can be manipulated ex-vivo, once re-infused into patients, the T cells are subjected to immunosuppressive mechanisms established by the tumor. An important immune checkpoint regulator within tumors is phosphatidylserine (PS). Innate immune cells exposed to PS secrete suppressive cytokines and chemokines that can significantly impair the function and activation of anti-tumor T cells. Therefore, monoclonal antibodies that block PS activity can increase the anti-tumor potency of transferred T cells to treat aggressive cancers. Here we show that a PS targeting monoclonal antibody in combination with CD4+ T cells that recognize the melanoma antigen Trp1 can regress very advanced melanomas in all treated mice. Combination of anti-Trp1 CD4+ T cells with other immunomodulatory modalities such as anti-OX40 antibodies, can achieve equivalent treatment rates but these are typically accompanied by severe immune related adverse events. In contrast, in this setting, PS blockade did not show any off-target toxicities. Flow cytometry analysis revealed lower levels of CD206 expression concomitant with higher activation markers in macrophages and neutrophils in tumors from anti-PS treated mice. These results suggest that diminishing suppressive mechanisms locally in adoptive transfer protocols is a highly desirable strategy that can eliminate tumors while minimizing related adverse events. Citation Format: Daniel Hirschhorn-Cymerman, Sara Sara Schad, Sadna Budhu, Zhong Hong, Xia Yang, Hutchins T. Jeff, Bruce D. Freimark, Michael J. Gray, Jedd Wolchok, Taha Merghoub. Targeting phosphatidylserine in combination with adoptive T cell transfer eliminates advanced tumors without off-target toxicities in a melanoma preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1651. doi:10.1158/1538-7445.AM2017-1651
Abstract 4880: MAGE gene family expression in pediatric medulloblastoma: frequency and possible therapeutic target
Authors: Rebecca R. Collins, Klementina Fon Tacer, Dinesh Rakheja, Patrick Ryan Potts
Journal: Cancer Research (2017)

Abstract Background: The melanoma antigen gene family (MAGE) is a group of related genes that were first discovered in malignant melanoma. Among the approximately 40 MAGE genes in the human genome, two thirds are classified as Type I (MAGE-A, MAGE-B, and MAGE-C), referred to also as cancer testis antigens (CTAs), proteins that are restricted to testis but often aberrantly expressed in many adult cancers. Despite their common expression in adult cancers and their oncogenic potential, little is known about their expression and role in pediatric cancers. To determine the frequency of MAGE expression in pediatric medulloblastoma, we measured expression levels of Type I MAGEs in patient tumors. In addition, we examined how MAGE expression in medulloblastoma cells affects their growth and oncogenic potential. Methods: We searched the Children’s Health pathology database for pediatric medulloblastoma between 2008 - 2015 and were able to recover an adequate amount of RNA from formalin-fixed paraffin-embedded tissue samples of 34 patients. The RNA was converted to cDNA using reverse transcriptase, and the relative expression of 23 Type I MAGE genes was measured by qRT-PCR. To determine if MAGE expression is critical for medulloblastoma cell survival we knocked down several MAGEs using siRNAs in two MAGE-expressing medulloblastoma cell lines (D283 and DAOY) and evaluated the effect by cell viability (Alamar Blue and Cell titer Glo), apoptosis assays (Annexin V), and colony formation in soft agar. Results: In 34 medulloblastoma patient samples we found that 10 (29.4%) expressed at least one MAGE gene, and one case had high levels of expression of 10 of the 23 Type I MAGEs. MAGE expression was associated with the non-WNT/SHH (G3/G4) molecular subgroup of tumors in our study. There was no correlation between MAGE expression and histologic subtype. Furthermore, using MAGE-A/-B2 positive medulloblastoma cell lines, we showed that siRNA knock down of multiple MAGE-As and -B2 decreased cell viability by 15 - 80%, increased apoptosis (-B2), and decreased growth of cells in soft agar. Conclusion: Type I MAGE genes are expressed in 30% of pediatric medulloblastoma in our study. In MAGE positive medulloblastoma cells, MAGE genes are important for cell survival and clonogenic growth. The decreased cell survival after MAGE knockdown appears to be related, at least in part, to increased apoptosis. Our results indicate that targeting of MAGEs in medulloblastoma may be a potential therapeutic option. Citation Format: Rebecca R. Collins, Klementina Fon Tacer, Dinesh Rakheja, Patrick Ryan Potts. MAGE gene family expression in pediatric medulloblastoma: frequency and possible therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4880. doi:10.1158/1538-7445.AM2017-4880
Abstract 3881: The expression of CD98hc might be a marker of radiation resistance in HNSCC
Authors: Yohei Kawasaki, Yasufumi Omori
Journal: Cancer Research (2017)

Abstract Introduction: Head and Neck squamous cell carcinoma(HNSCC) represents an aggressive malignancy. Although new advanced therapeutic strategies have been applied to date, the 5-year survival rate have not been considerably improved. Generally speaking, high radio-sensitive HNSCC has good prognosis, however, there are radio-resistant HNSCC. Recently, Sanne et al, have reported CD98 is one of the marker of Cancer Stem Cell. Moreover, the over expression of CD98hc is high associated with different cancers including the colon cancer, renal cancer. CD98 is heterodimeric protein that comprises a heavy chain and a light chain. The CD98 heavy chain is type 2 linkage to one of 6 amino acid transporters. We hypothesize that irradiation may contribute to overexpression of CD98hc and expansion Cancer Stem Cell population in HNSCC. Methods:cell culture: Ho-1-u-1(Mouth floor), Sa3(Gingiva), HSC2, HSC3,HSC4(tongue) were used for this experiment. These cell lines were exposed to 60 Gy (2Gy/day) to establish stable cell lines to radiation.Flow cytometry: For analysis of CD98-positive fraction, cell pellets were incubated with FITC-conjugated anti-human CD98hc mAb at the dilution of 1:11 at 4°C for 15min.Sphere formation assay: Cells were cultured in a serum-free medium. 1x104 cells were seeded in 80μl of serum free RPMI1640 medium. The recipe of which was mentioned above. Containing 1.0% agar on 100μl of a solidified serum free RPMI1640 was poured on the top of each well. The cells were incubated for 20 days in the same atomosphere as that for the monolayer culture.Migration Assay: Radius 24 well Cell Migration (Cell Biolabs, INC.) were purchased. The experiment was conducted according to the decided plotocol. Result: In radiation resistant cells, spindle-shaped and large cytoplasmic cells were founded. After irradiation, the expression of CD98hc increased in all cell lines. In Ho-1-u-1, the population was divided into two distinct subpopulations showing a higher and a lower expression of CD98hc. Irradiated cancer cells exhibit an efficient ability to developed numerous large sphere. Irradiation had enhanced self-renewal of Cancer Stem Cells. Cell motility was higher in radio-resistant cells than their parental cells. Conclusion: Radio-resistant cells overexpressed CD98hc. In other words, CD98hc may be a marker of radiation resistance. Since incomplete radiation therapy can expand Cancer Stem Cell population, so elucidation of mechanism of radiation resistance will improved radiotherapy. CD98hc might be the target for more efficient treatment. Citation Format: Yohei Kawasaki, Yasufumi Omori. The expression of CD98hc might be a marker of radiation resistance in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3881. doi:10.1158/1538-7445.AM2017-3881