tbuckley/cabot-search huggingface dataset:
Abstract 3090: Molecular structure of the major G-quadruplex formed in the PDGFR-β promoter nuclease hypersensitivity element and its binding with small molecules
Authors: Clement Lin, Prashansa Agrawal, Yuwei Chen, Salil Kalarn, Nanjie Deng, Laurence Hurley, Danzhou Yang
Journal: Cancer Research (2016)

Abstract Overexpression of platelet-derived growth factor receptor β (PDGFR-β) is associated with multiple cancers, making PDGFR-β an attractive target for anticancer drugs. Few strategies other than molecular targeting of the PDGFR-β protein or its cognate ligand have been reported for developing inhibitors for the PDGFR-β signaling pathway. DNA G-quadruplexes (G4s) formed in the GC-rich nuclease hypersensitivity element of the human PDGFR-β gene promoter have been found to inhibit PDGFR-β transcriptional activity, and stabilization of these G4s by small-molecule compounds could serve as a mechanism for cancer therapeutics. We have shown that the major G4 formed in the PDGFR-β promoter is from the central four G-runs, adopting an intramolecular parallel-stranded structure with a broken G-strand and contains three 1-nucleotide (nt) chain-reversal loops and one lateral loop. The novel folding of the PDGFR-β G4 highlights the inherent stability of the 1-nt loops in parallel-stranded G4 structures. Elucidating the structure of the major PDGFR-β promoter G4 is important for designing small-molecule drugs to specifically target this structure to inhibit gene transcription. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the potassium solution structure of this major G4 formed in the PDGFR-β promoter. Our structure showed a unique 3’ capping structure involving three guanine nucleotides in the lateral loop. This novel capping structure is determined by the specific loop sequence as well as the broken-stranded PDGFR-β G4 folding pattern. The unique 3’ capping structure could be specifically recognized by proteins and small molecule ligands. Unrestrained molecular dynamic calculations showed that this major PDGFR-β G4 and its 3’ capping structure are stable in aqueous environment on the ns time-scale. We also investigated the binding of small-molecules to the PDGFR-β G4 using a combination of NMR, circular dichroism (CD), and fluorescence based methods to identify compounds that can selectively bind the PDGFR-β G4 over other classic parallel-stranded G-quadruplexes, such as the c-MYC promoter G4. Our study demonstrates the structural diversity in promoter G4s which may enable specific recognition and the modulation of gene expression by small-molecule drugs. Citation Format: Clement Lin, Prashansa Agrawal, Yuwei Chen, Salil Kalarn, Nanjie Deng, Laurence Hurley, Danzhou Yang. Molecular structure of the major G-quadruplex formed in the PDGFR-β promoter nuclease hypersensitivity element and its binding with small molecules. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3090.
BGB324 Inhibits BCR-ABL TKI-Resistant Chronic Myeloid Leukemia
Authors: Isabel Ben Batalla, Robert Erdmann, Heather Jørgensen, Rebecca Mitchell, Thomas Ernst, Gunhild von Amsberg, Philippe Schafhausen, Stephen Rankin, Richard E. Clark, Steffen Koschmieder, Alexander Schultze, Subir Mitra, Peter Vandenberghe, Tim H. Brümmendorf, Peter Carmeliet, Gudmundur Helgason, Andreas Hochhaus, Klaus Pantel, Carsten Bokemeyer, Tessa L Holyoake, Sonja Loges
Journal: Blood (2015)
Rice Varieties in Archaic East Asia: Reduction of Its Diversity from Past to Present Times
Authors: Masahiko Kumagai, Masaaki Kanehara, Shin’ya Shoda, Saburo Fujita, Shizuo Onuki, Shintaroh Ueda, Li Wang
Journal: Molecular Biology and Evolution (2016)

The Asian cultivated rice, Oryza sativa, is one of the most important crops feeding more than a third of global population. In spite of the studies for several decades, the origin and domestication history of rice varietal groups, japonica and indica, have not been fully unveiled. Genetic information of ancient rice remains is essential for direct and exclusive insight into the domestication history of rice. We performed ancient DNA analysis of 950- to 2,800-year-old rice remains excavated from Japan and Korea. We found the presence of both japonica- and indica-type varieties in the Yayoi period and the middle ages of Japan and the middle part of Korea Peninsula 2,000 years ago. It is popularly considered that japonica has been exclusively cultivated in northern part of East Asia including Japan and Korea. Our result disclosed unexpectedly wide diversity of rice varieties in archaic East Asia. The present results from ancient rice DNA reveal an exclusive insight for the domestication history of rice which is not provided as far as contemporary rice.
Variation in policy and practice of adolescent tuberculosis management in the WHO European Region
Authors: Nick Blok, Martin van den Boom, Connie Erkens, Masoud Dara, Susan van den Hof
Journal: European Respiratory Journal (2016)

Tuberculosis (TB) is a major public health concern worldwide. The World Health Organization (WHO) estimates that 9.6 million people fell ill with TB and 1.5 million people died of TB in 2014. Of an estimated total of 1 million children with TB, 140 000 children died [1]. The risk of progression to TB is highest for children <5 years of age. There is a comparatively low risk for those 5–10 years of age, after which the risk of progression to TB increases at the onset of puberty to an adult level of 5–10% [2] as well as the chance of developing an adult-type TB accompanied by increased infectiousness [3]. However, adolescents form a particularly vulnerable group with psychosocial challenges distinct from adults and the usual challenges of transition from paediatric to adult health service provision. Puberty may affect health behaviour and have a significant impact on therapy compliance [4], requiring specific approaches usually not provided by paediatric or adult health services [5]. Guidelines specifically addressing adolescent tuberculosis are needed for uniform and evidence-based management <http://ow.ly/BMm63015LcY>
Abstract 5057: Mena at the nexus of chemotaxis and haptotaxis during tumor progression
Authors: Madeleine J. Oudin, Miles A. Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas Lauffenburger, James E. Bear, Frank B. Gertler
Journal: Cancer Research (2016)

Abstract Directed-cell migration is key step in the metastatic cascade, and multiple cues can promote local invasion. The most well studied mode of cell motility for metastasizing tumor cells is chemotaxis, the directional movement of cells attracted to a source of soluble cues. In contrast, haptotaxis, migration of cells on gradients of substrate-bound factors, remains poorly understood. Mena, an actin regulatory protein, plays an important role in cell motility and is upregulated in various cancers, driving migration in response to chemotactic and haptotactic cues. We have recently shown expression of the pro-metastatic isoform of Mena, MenaINV, increases sensitivity to growth factors (EGF, HGF and IGF) via dysregulation of the phosphatase PTP1B, as well as high concentrations of fibronectin (FN) via its interaction with the integrin α5β1. We hypothesized that MenaINV may also promote crosstalk between these two pathways to drive metastasis. First, we show that MenaINV-driven haptotaxis on FN gradients and FN-driven invasion requires crosstalk between α5β1 and EGFR. Indeed, we show evidence that MenaINV expression is associated high phosphorylation of EGFR in high FN environments in vitro and in human breast cancer databases. Second, we find that MenaINV promotes synergy between EGF and FN in vitro and in vivo, leading to hyper-invasive phenotypes that drive more invasion than which each cue alone. Finally, we show that MenaINV-driven haptotaxis, ECM reorganization and 3D invasion requires RCP-dependent recycling of α5β1 and EGFR. Together, our data demonstrate that MenaINV is a shared component of the machinery that mediates both haptotactic responses to FN and chemotactic responses to EGF, two pathways that promote tumor progression. Citation Format: Madeleine J. Oudin, Miles A. Miller, Tatsiana Kosciuk, Joelle Klazen, Alisha Lussiez, Douglas Lauffenburger, James E. Bear, Frank B. Gertler. Mena at the nexus of chemotaxis and haptotaxis during tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5057.
Abstract 3060: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib
Authors: Brian B. Hasinoff, Xing Wu, Daywin Patel
Journal: Cancer Research (2016)

Abstract Bortezomib and carfilzomib are anticancer drugs that target the proteasomal system. Case reports indicate that the use of these drugs can result in cardiotoxicity. These drugs may also be used in combination with doxorubicin, which is itself cardiotoxic. Thus, in order to determine the mechanism of this cardiotoxicity studies were undertaken using a neonatal rat myocyte primary cell model. Using LDH release as a measure of damage in the myocyte model we showed that even brief exposure (6 h) to submicromolar concentrations of bortezomib resulted in significant myocyte damage. Carfilzomib was slightly less toxic and displayed myocyte damage in the low micromolar concentration range. Utilizing a fluorogenic substrate both bortezomib and carfilzomib inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the submicromolar concentration range. The inhibition kinetics were consistent with formation of an essentially irreversible covalent complex at the active site. Bortezomib irreversibly inhibited proteasomal activity about four-fold faster than carfilzomib. Thus, the reduced toxicity of carfilzomib may be due to its slower inhibition kinetics. A brief pre-exposure (6 h) of myocytes to low non-toxic nanomolar concentrations of bortezomib greatly increased doxorubicin-mediated damage. The doxorubicin cardioprotective agent dexrazoxane partially protected the myocytes from doxorubicin treatment and from bortezomib plus doxorubicin treatment under these conditions. However, at slightly toxic bortezomib concentrations dexrazoxane offered little protection against bortezomib plus doxorubicin treatment. Bortezomib, at least over short times, did not induce oxidative damage in myocytes as measured with a fluorogenic DCF assay. Likewise, a 6 h bortezomib treatment did not affect the mitochondrial membrane potential of myocytes as measured in a JC-1 ratiometric assay. In conclusion both bortezomib and carfilzomib are potently toxic to myocytes at submicromolar concentrations, likely through their ability to irreversibly inhibit myocyte proteasomal activity. Support: CIHR; a Canada Research Chair in Drug Development. Citation Format: Brian B. Hasinoff, Xing Wu, Daywin Patel. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib and carfilzomib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3060.
Abstract 63: Absence of Fibulin-2 Attenuates Cardiac Hypertrophy and Fibrosis in Transgenic Mice Over-expressing Circulating Transforming Growth Factor-beta
Authors: Takeshi Tsuda, Shaukat Khan
Journal: Circulation Research (2015)

Background: TGF-β is a potent growth factor that induces myocardial hypertrophy and fibrosis. However, the interaction between circulating TGF-β and local myocardial TGF-β in inducing cardiac hypertrophy is not well understood. Fibulin-2 is an ECM protein that mediates TGF-β activation during cardiac hypertrophy in response to chronic angiotensin (Ang) II infusion. We tested the hypothesis that fibulin-2 mediates systemic TGF-β-induced cardiac hypertrophy. Materials &amp; Methods and Results: We created double mutant mice by crossing TGF-β over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG are known to produce excessive mature porcine TGF-β from the liver. TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in KO/TG was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA up-regulation was significantly higher in TG/WT than in TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity measured by PAI-1 promoter/luciferase bioassay was comparable among all four groups. Serum carrier-bound TGF-β (total TGF-β) in WT/TG was significantly higher than that in KO/TG and NTG groups, but free TGF-β level was equally elevated in TG groups compared with NTG groups. The difference in hypertrophy between WT/TG and KO/TG may be attributed to increased myocardial TGF-β[[Unable to Display Character: &amp;#61472;]]mRNA and elevated serum total TGF-β in WT/TG, not directly to bioactive myocardial TGF-β[[Unable to Display Character: &amp;#61472;]]or serum free TGF-β. Endogenous TGF-β mRNA levels in kidney and liver were equally increased in TG groups compared with NTG groups, and were same in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in these organs. Conclusion: Systemic TGF-β-induced-endogenous TGF-β up-regulation was mediated by fibulin-2 in the myocardium. After secretion, endogenous myocardial TGF-β may be either sequestrated into insoluble ECM or directly released into circulation as a soluble carrier-bound form. It is circulating endogenous TGF-β secreted from the heart that is primarily responsible for myocardial hypertrophy. Heart is a major source of circulating endogenous TGF-β in the TG/WT, which assumes an endocrine role in inducing myocardial hypertrophy.
Abstract 741: Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis
Authors: Tiffany Scully, Carolyn D. Scott, Hasanthi C. de Silva, Sue M. Firth, Stephen M. Twigg, John E. Pintar, Robert C. Baxter
Journal: Cancer Research (2016)

Abstract Introduction and Aim: Epidemiological studies have shown an association between obesity and poor breast cancer prognosis. We have reported that IGFBP-3 influences both breast cancer growth and adipocyte maturation. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth. Methods: Wild-type (WT) C57BL/6 or IGFBP-3 knock-out (BP3KO) mice were fed either a high-fat diet (HFD) or control chow diet for 15 weeks, then injected with the syngeneic mouse breast cancer cell line E0771 in the 4th left mammary gland. When the largest tumor reached 1000 mm3, tissues including the mammary fat pad were excised, formalin-fixed and paraffin-embedded for immunohistochemical analysis. Results and Conclusion: Compared to WT mice, BP3KO mice showed both significantly reduced weight gain and mammary fat pad mass (contralateral to tumor) in response to HFD (p &amp;lt; 0.0001, 1-way ANOVA), despite similar food intake between WT and BP3KO mice on HFD. E0771 tumor weight and volume were overall increased by HFD independent of IGFBP-3 status (p = 0.051), and decreased in BP3KO mice independently of diet (p &amp;lt; 0.001, 2-way ANOVA). Despite differences in tumor volumes and weights, tumors from WT and BP3KO mice did not show differences in either the number of mitotically active (Ki67+) or apoptotic (cleaved caspase-3+) cells. Tumors from BP3KO mice however, showed greater infiltration of CD3+ T-cells compared to WT mice (p = 0.0299, 2-way ANOVA). WT and BP3KO mice showed similar intra-tumoral mean vessel densities (CD31+ area) but differed in terms of the relationship between vessel density and final tumor volume. Increased vessel density was associated with decreased tumor volume in BP3KO mice (r = -0.62, p = 0.03, Spearman's correlation test) in contrast to the increased vessel density associated with increased tumor volume in wild-type mice (r = 0.63, p = 0.02, Spearman's correlation test). These data suggest that endogenous (circulating and/or stromal) IGFBP-3 (i) has a potentially stimulatory role in the expansion of adipose tissue, (ii) can enhance mammary tumor growth in immune-competent mice, potentially by influencing T-cell infiltration into the tumor and (iii) may influence the relationship between tumor vascularity and growth. Citation Format: Tiffany Scully, Carolyn D. Scott, Hasanthi C. de Silva, Sue M. Firth, Stephen M. Twigg, John E. Pintar, Robert C. Baxter. Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 741.
Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase.
Authors: A. Jimeno, R. S. Herbst, G. S. Falchook, W. A. Messersmith, S. Hecker, S. Peterson, D. F. Hausman, R. Kurzrock, S. G. Eckhardt, D. S. Hong
Journal: Journal of Clinical Oncology (2010)

3089 Background: Increased signaling through the PI3 kinase pathway is relevant in multiple cancers. PX-866, derived from wortmannin, is an irreversible pan-inhibitor of class 1A and B PI3 kinases active in a variety of tumor models. PX-866 was tested in a phase I dose escalation study in patients with advanced solid tumors. Methods: Using a 3+3 design, pts received escalating doses of PX-866 orally once daily on days 1-5 and 8-12 of a 28 day cycle (intermittent schedule) with an expanded cohort at the MTD. Evaluation of daily PX-866 (continuous schedule) began once MTD was determined for the intermittent schedule. Assessments include safety, response, pharmacokinetics (PK), and pharmacodynamics (PD) in peripheral blood mononuclear cells (PBMCs) and tumor. Archived tissue was tested for PIK3CA and KRAS mutations and PTEN deletions. Results: 52 pts (age 41-83; median ECOG PS 1) have been treated: 39 in intermittent schedule dose escalation (doses 0.5 to 16 mg), 10 in MTD expansion (dose 12 mg), and 3 in continuous schedule dose escalation. MTD for the intermittent schedule was 12 mg; DLTs at 16 mg were diarrhea (n=2) and ALT/AST elevation (n=1). Most AEs were Gr 1/2, including nausea, vomiting, and diarrhea. 16 pts had ≥Gr 3 AEs, with 4 related to study drug (n=1 each): diarrhea, increased AST, anorexia, and hypertension. No changes were seen in hematologic parameters, insulin or glucose levels. PD in PBMCs showed inhibition of S6 ribosomal protein and mTOR phosphorylation. PK is consistent with rapid conversion to an active metabolite. Best response has been SD in 7/31 evaluable pts (received ≥1 cycle or had documented PD). All 7 received ≥4 cycles (anaplastic thyroid, hepatoid, melanoma, squamous skin, NSCLC, chondrosarcoma, and adenoid cystic cancers). 11 additional pts are active and not yet assessed. Enrollment in the expansion cohort is complete, and dose escalation in the continuous schedule has begun, with no DLTs at 8 mg daily. Conclusions: PX-866 was well tolerated, and the intermittent schedule MTD is 12 mg. Final safety, efficacy, PK, and PD results from this first-in-human study will be presented. Inhibition of PI3 kinase pathway activity and SD in heavily pretreated patients supports phase II testing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncothyreon Oncothyreon Oncothyreon Oncothyreon Oncothyreon
Abstract 2120: Molecular characterization of cancer stem cells derived from drug-resistant melanoma
Authors: Elyse J. Berlinberg, William Crosson, Arbis Rojas, Ramin Nazarian
Journal: Cancer Research (2016)

Abstract BRAF kinase is a key intermediate in the MAP kinase pathway, which is associated with cell growth and proliferation. BRAFV600E activating mutation is found in 50-60% of all melanomas and 7% of all cancer malignancies. Despite an unprecedented initial response, patients treated with a highly effective BRAF inhibitor, vemurafenib (FDA approved 2011), can acquire drug resistance in as little as 6-9 months. Epigenetically driven epithelial-to-mesenchymal transition (EMT), a hallmark of cancer stem-like cells (CSCs), is a potential mechanism that melanomas employ to evade targeted therapy. We are investigating molecular alterations due to EMT in parental and vemurafenib-resistant melanoma sublines. Characterization of differential protein expression in parental and resistant cell lines through immunocytochemical, flow cytometric, and immunoblot analysis has indicated that EMT could confer drug resistance that prolongs survival of malignant melanomas. Furthermore, comparison of parental to isogenic resistant melanoma cell lines showed upregulated expression of EMT-related biomarkers that may be suggestive of the development of CSCs. These CSCs may serve as progenitor cells for therapy-resistant sublines in a heterogeneous melanoma population. Our research has identified notable EMT biomarkers in CSCs that can be used as novel targets for diagnosis and treatment of tumor resistance in melanoma patients. Citation Format: Elyse J. Berlinberg, William Crosson, Arbis Rojas, Ramin Nazarian. Molecular characterization of cancer stem cells derived from drug-resistant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2120.