bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-240: Clustering of phospho-proteins targeted by enzastaurin identifies significant biomarker association with patient outcome and novel associations between biomarker groupings in a glioblastoma multiforme cohort
Authors: Dolled-Fillhart Marisa , Pinard Robert , Waldron Don , Ang Agnes , Goodrich Leo , Myrand Scott , Thornton Don , Graff Jeremy , Mullaney Brian 
Published: May 2019

Abstract
Introduction: Enzastaurin (LY317615.HCl) is a novel acyclic bisindolylmaleimide currently in Phase II clinical trials in combination with temozolomide and radiation for the front-line treatment of glioblastoma multiforme. Enzastaurin was identified as an ATP-competitive inhibitor of PKC-β subsequently as an inhibitor of other AGC-family kinases, including other PKC isoforms, p90RSK, GSK3β, and p70S6K. In a wide array of human cancer cell lines, including glioblastoma cell lines, enzastaurin treatment blocks signaling through the PI3 kinase/AKT/mTOR pathway. Accordingly, enzastaurin suppresses the phosphorylation of GSK3Bser9, AKTser473, CREBser133, and the S6 ribosomal protein at ser235/236 and ser240/244. We therefore sought to evaluate the levels of these key phosphorylation events in a series of primary human glioblastoma multiforme tissues in order to determine whether any or all of these phosphorylation events might be related to patient survival.
Methods: A retrospective glioblastoma multiforme cohort of 115 patients was evaluated by quantitative immunofluoresence using AQUA® analysis for PhosphoCREB ser133, PhosphoS6 ser240/244, PhosphoGSK3B ser9, and total GSK3B. AQUA® technology quantitatively measured protein expression in patient samples, allowing for relative concentrations of the phosphorylated markers to be calculated and grouping of patients by clustering of AQUA® scores.
Results: Spearman-Rho analysis identified strong direct correlations between PhosphoCREB ser133 and PhosphoS6 ser240/244 and between PhosphoCREB ser133 and PhosphoGSK3Bser9 expression in this cohort of patients. Univariate Kaplan Meier survival analysis of these patients based on clustered AQUA® scores revealed that these markers were indeed inversely related to disease-specific survival (phosphoGSK3B ser9 P&lt;0.05). Multiparametric Correlative Discovery™ analysis also indicated a strong association of the cluster of patients with low levels of phosphoprotein expression and better survival. Conclusions: These data reveal that the signaling pathways targeted by enzastaurin were activated specifically in patients with the poorest survival and also suggest that these phosphomarkers, alone or in concert, may be useful for patient stratification.
Abstract LB-247: A multidisciplinary phase II study of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma
Authors: Batchelor Tracy T , Sorensen Gregory , di Tomaso Emmanuelle , Duda Dan G , Zhang Wei-Ting , Ancukiewicz Marek , Lahdenranta Johanna , Louis David , Plotkin Scott , Ivy Percy , Loeffler Jay S , Wen Patrick , Jain Rakesh K 
Published: May 2019

Abstract
Targeted agents are promising new therapeutics that have entered clinical trials for glioblastoma. AZD2171 (cediranib) is a potent, oral pan-VEGF receptor tyrosine kinase inhibitor with a half-life of 20 hours compatible with once-daily dosing. A primary target of AZD2171, VEGFR2, is expressed on glioblastoma endothelium. We have demonstrated normalization of tumor vessels in recurrent glioblastoma patients administered AZD2171 on a daily basis. Normalization has rapid onset, is reversible, and is associated with alleviation of brain edema (Batchelor TT, et al. Cancer Cell 2007;11:83-95). In this Phase II study of 31 recurrent glioblastoma subjects we now report clinical outcomes, including the proportion of patients alive and progression-free at 6 months (APF6) as the primary endpoint. Secondary endpoints include radiographic response proportion; progression-free survival; and overall survival and toxicity. At this time we are presenting radiographic response data, APF6, PFS, and OS on 31 patients. Thirty patients have experienced disease progression and one patient remains in follow-up without progression. The primary and secondary endpoints are tabulated below:
Radiographic Responses Partial Response (more than 50% decrease in volume) in 16/30 (56%)
APF6 [95% CI] 25.8% [14.7%, 46.9%]
PFS [95% CI] 117 days [88, 145]
OS [95% CI] 221 days [172, 285]
Only one of the first 16 patients was removed from the study due to toxicity (fatigue). Dose limiting toxicities were observed in 9/16 patients with hypertension; fatigue and diarrhea were encountered most often. There have been no intracerebral hemorrhages. AZD2171 alleviated brain edema, a major cause of morbidity in glioblastoma patients, and had a steroid-sparing effect in many of the patients enrolled. Blood biomarkers were serially assessed and it was observed that plasma VEGF, PlGF, and SDF1α were increased after treatment. Plasma PlGF and VEGF decreased upon cediranib discontinuation. Plasma bFGF and SDF1α and viable circulating endothelial cells increased when tumors escaped treatment with AZD2171. AZD2171 is a promising therapy for glioblastoma and an attractive therapeutic partner for chemotherapy or radiation.
Abstract LB-330: A novel role of tumor suppressor BRCA1 in regulating integrity of heterochromatin structure.
Authors: Zhu Quan , Pao Gerald , Tonnu Nina , Verma Inder M 
Published: May 2019

Abstract
Introduction: BRCA1, as well as BRCA2, were identified as the hereditary breast and ovarian cancer susceptibility genes that can account for almost all of inherited cases of breast cancers. BRCA1 is a multifunctional nuclear protein with a RING domain at the N-terminus. Heterochromatin is chromatin containing inactive genes. Pericentromeric heterochromatin is composed of highly repetitive tandem DNA repeats whose transcription is constitutively silenced. In mice, the repeats are classified as major and minor satellite repeats. Heterochromatin protein 1 (HP1) plays a critical role in maintaining heterochromatin structure.
Methods: To study the biological function of the tumor suppressor BRCA1, we deleted BRCA1 in nestin positive neuronal stem cells in the brain and showed that the animals displayed severe neuro-developmental deficits. In the course of this work we discovered a novel molecular defect in BRCA1 deficient cells, i.e., a failure to maintain integrity of the heterochromatic structure.
Results: In the absence of BRCA1, the number of heterochromatic centers is severely reduced in mouse neuronal cells. HP1 proteins are destabilized, and more importantly, the transcription of satellite DNA is derepressed in mouse neural progenitor cells, mouse fibroblasts, and human cancer cells, including a BRCA1 deficient breast cancer cell line. The defect in silencing invariably appears after the loss of the BRCA1 allele in our paradigm prior to exhibiting any neoplastic phenotype. What is the mechanism of BRCA1 in regulating the heterochromatin integrity? ChIP analysis showed that BRCA1 physically associates with both major satellite DNA and minor satellite DNA, whereas the association is diminished in the BRCA1 knockout animals. More intriguingly, the absence of BRCA1 binding to satellite DNA correlates with a drastic reduction of ubiquitinated histone H2A at the constitutive heterochromatin region. Because BRCA1 contains an E3 ubiquitin ligase activity which is enhanced by BARD1 and the complex ubiquitinate histone H2A in vitro, we examined the heterochromatin silencing in cells with different BRCA1 mutants. These experiments showed that the E3 ligase activity of BRCA1 is required for repression of satellite DNA transcription.
Conclusions: Our working model is that mutations of BRCA1 may destabilize the protein complex and lead to defects in the heterochromatin integrity, thereby affecting the stability of the genome which is a hallmark of cancer. Given that mutants in the RING domains are the same as in women who have pathological diseases, we hypothesize that deregulation of satellite DNA transcription can be explored as an early detection marker for breast cancer progression in BRCA1 patients.
Abstract LB-332: A novel TIMP-2-mediated cytoplasmic mechanism for the regulation of receptor tyrosine kinase, VEGFR-2
Authors: Sivendran Renuka , Li Hongmei , Seo Dong-Wan , Diaz Tere , Wei Beiyang , Stetler-Stevenson William G. 
Published: May 2019

Abstract
The vascular endothelial growth factors (VEGFs) and their receptors (receptor tyrosine kinases) are critical for angiogenesis. The binding of VEGF-A induces dimerization and autophosphorylation of its receptor, VEGFR-2. This initiates a signaling cascade that results in increased cell proliferation, migration, and permeability. The introduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) protein or a dominant negative mutant that has no MMP inhibitory activity (Ala+TIMP-2) intercepts this signaling cascade and affects these cellular functions. To elucidate the mechanisms of this disruption in VEGFR-2 signaling, we explored direct (competition binding, substrate affinity, total binding capacity) and indirect (receptor degradation, receptor dimerization by cross-linking, and FRET) mechanisms that could facilitate the inhibition of growth factor signaling by TIMP-2. Our studies showed that TIMP-2 did not directly compete for binding to VEGFR-2 as previously reported for TIMP-3 (Qi JH. Nature Medicine 2003;9:407-15). Further, TIMP-2 did not increase the internalization and degradation of VEGFR-2, nor did it decrease the affinity of the VEGF-A ligand. In contrast, TIMP-2 decreased the total cellular binding capacity for VEGF-A. These data suggest a novel mechanism by which TIMP-2 may regulate the binding conformation or state of VEGFR-2 dimerization, thereby influencing the cell sensitivity to VEGF-A stimulation. To study the conformation or state of VEGFR-2 dimerization, we conducted cross-linking analysis of VEGFR-2, and the results showed that TIMP-2 pretreatment prior to VEGF-A treatment significantly decreased VEGFR-2 dimer formation. In order to study this quantitatively, we designed a fluorescence resonance energy transfer (FRET) system that would detect the intracellular dimers of VEGFR-2. We fused Cerulean or Venus to the C-terminus of human VEGFR-2, transfected porcine aortic endothelial (PAE) cells, and selected stable cells expressing the constructs. Sensitized emission FRET analysis of the transfected PAE cells showed that Ala+TIMP-2 pretreatment prior to VEGF-A treatment decreased the VEGFR-2 dimerization to basal levels. This demonstrated that TIMP-2 regulates the binding capacity of VEGFR-2 by modulating the monomer-dimer equilibrium of VEGFR-2. This is the first demonstration of a cytoplasmic signaling mechanism influencing the monomer-dimer equilibrium of a receptor tyrosine kinase. This may potentially be a common mechanism for cellular regulation of growth factor sensitivity for this class of receptor tyrosine kinases.
Abstract LB-334: Signals from the microenvironment induce a malignant program accompanied by de novo epigenetic remodeling
Authors: Dumont Nancy , Crawford Yongping G. , Reynolds Paul A. , Wilson Matthew B. , Sigaroudinia Mahvash , Gauthier Mona L. , Fordyce Colleen A. , Tlsty Thea D. 
Published: May 2019

Abstract
Introduction: The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has recently demonstrated that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenetic remodeling resulting in the targeted methylation of selected CpG islands. We hypothesized that cells in this epigenetically-plastic state can be programmed by the microenvironment to acquire epigenetic changes that promote tumorigenesis.
Methods: Normal human mammary epithelial cells (HMEC) and HMEC with repressed p16 were first transduced with constitutively active Ha-rasV12. In order to mimic the secretory aspects of the extracellular environment, the cells were subsequently cultured in a serum-rich environment.
Results: When p16-repressed cells were challenged with oncogenic stress, they failed to undergo the classic proliferative arrest as documented in normal cells. When further stressed by being cultured in a serum-rich environment, they spontaneously immortalized and exhibited phenotypic changes indicative of epithelial to mesenchymal transition (EMT). The EMT was accompanied by de novo methylation of the E-cadherin promoter and increased motility.
Conclusions: These data demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes that result in de novo epigenetic alterations important in tumor progression.
Abstract LB-78: A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma
Authors: Wu Kana , Platz Elizabeth A , Willett Walter C , Selhub Jacob , Fuchs Charles S , Giovannucci Edward 
Published: May 2019

Abstract
Results from two recently published randomized trials (Logan et al., 2008 and Cole et al., 2007) found little evidence for a protective effect of folic acid supplementation on the recurrence of colorectal adenomas. In one trial (Cole et al., 2007) folic acid supplementation even appeared to be non-significantly associated with higher risk of advanced adenoma. This following paper reports on results from another randomized controlled trial of folic acid (1000 micrograms/day) versus placebo among participants of two large prospective cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), who had a previous diagnosis of colorectal adenoma. The primary endpoint of interest was any new diagnosis of adenoma during the study period (May, 1996 to March, 2003). 346 subjects were randomized to folic acid and 346 subjects to placebo for a period of three to up to 6 1/2 years. The incidence of at least one recurrent adenoma was not associated with folic acid supplementation (RR=0.86, 95% CI=0.64-1.16, p=0.32). There was some suggestion of an inverse association between folic acid supplementation and recurrent distal adenoma (multivariate adjusted relative risk (RR) =0.67, 95% confidence interval (CI)=0.39-1.15, p=0.14), and early stage adenoma (small and tubular) (RR=0.74, 95% CI=0.48-1.15, p=0.19), but none of the associations reached statistical significance. Advanced adenoma (large or adenomas with villous component) was not associated with folic acid supplementation, but the number of advanced cases was low (16 cases folate group, 18 cases placebo group; RR=0.96 95% CI=0.50-1.84, p=0.90). However, when associations were examined by folate blood concentrations drawn prior to time of randomization (&lt;=7.5 ng/mL vs. &gt;7.5 ng/mL) significant inverse associations were found for total recurrent adenoma (43 cases placebo, 32 cases folate, RR=0.64 (95% CI=0.43-0.96, p=0.03), distal adenoma (20 cases placebo, 9 cases folate, RR=0.36 (95% CI=0.14-0.61, p=0.001), early adenoma (22 cases placebo, 10 cases folate, RR=0.36 (95% CI=0.17-0.76, p=0.007), advanced adenoma (14 cases placebo, 9 cases folate, RR=0.48 (95% CI= 0.22-1.06, p=0.07) among those with low folate levels. No associations were found for participants with higher folate levels at baseline (at least one adenoma: 30 cases placebo, 30 cases folate, RR=1.30 (95% C=0.83-2.03, p=0.25). Occurrence of deaths, cancer and cardiovascular disease did not differ by treatment status. Our results do not support a protective effect of folic acid supplementation on the recurrence of colorectal adenomas; however, there may be some benefit on adenoma recurrence among those with a lower folate levels at baseline. The role of additional folic acid supplementation as a potential preventive measure for colorectal adenomas/cancer needs to be reevaluated especially with regard to dose and timing.
Abstract P1-07-06: Immune signatures define and affect prognosis in triple-negative breast cancer subtypes
Authors: Bottai G , Balazs G , Nagy A , Pusztai L , Szallasi Z , Reis-Filho JS , Santarpia L 
Published: May 2019

Abstract
Background: The tumor immune microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patient's prognosis and response to therapies. Triple negative breast cancer (TNBC) is a heterogeneous disease in which different genomic subgroups have been described (Lehmann, et al. J Clin Invest.2011). Our aim was to integrate the composition of the tumor immune microenvironment with the molecular TNBC subtypes.
Methods: We retrospectively analyzed the composition and the functional orientation of the immune microenvironment of 963 TNBC tumors clustered in 4 main TNBC subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], Mesenchymal/Mesenchymal Stem-Like [MS], Androgen Receptor [AR]) from independent cohorts using transcriptomic profiling. TNBC were stratified based on 9 different immune signatures (Natural Killer [NK], Dendritic Cells [DC], T-Cells [TC], B-Cells [BC], T-Cytotoxic [TC], Interferon [IF], Nuclear Factor-kB [NF-kB], anti-tumor Macrophages [M1] and pro-tumor Macrophages [M2]. We validated our findings using immunohistochemistry.
Results: We report that TNBC molecular subgroups and specific microenvironmental immune signatures are highly correlated. The IM was enriched of almost all the immune modules. On overall TNBC population, the TC (P = 0.01), IF (P = 0.007) and M1 (P = 0.001) signatures were associated with good prognosis. The BL subgroup with a good prognosis was characterized by overexpression of genes specific to M1-macrophages (P = 0.004) and TC-lymphocytes (P = 0.01). In contrast, the poor-prognosis MS expresses markers of cells of monocytic origin and significantly associated with the M2 signature (P = 0.01). The MS subgroup also displays an inflammatory and immunosuppressive signature. Pathological examination revealed that the MS subtype is characterized by a high density of pro-tumor macrophages that likely produce chemokines and cytokines which favor tumor-associated inflammation, resulting in a poor prognosis. In contrast, the AR exhibits low immune and inflammatory signatures.
Conclusions: The distinct immune orientations of the TNBC molecular subtypes pave the way for tailored immunotherapies.
Citation Format: Bottai G, Balazs G, Nagy A, Pusztai L, Szallasi Z, Reis-Filho JS, Santarpia L. Immune signatures define and affect prognosis in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-06.
Abstract P2-01-27: Sentinel lymph node biopsy by contrast-enhanced ultrasonography with sonazoid in patients with breast cancer - Prospective multicenter study
Authors: Shimazu K , Ito T , Uji K , Miyake T , Motomura K , Noguchi S 
Published: May 2019

Abstract
Background: The aim of this prospective study is to evaluate feasibility of the periareolar injection of contrast agent (Sonazoid (SNZ)) followed by ultrasonography (US) for identification of sentinel lymph node (SLN) in breast cancer patients with clinically negative node.
Patients and Methods: Patients with T1-2N0M0 breast cancer were recruited in this study. They received the periareolar injection of SNZ followed by US to identify contrast-enhanced SLN. Fine needle aspiration biopsy (FNAB) was done for each CE-SLN. Then, they underwent SLN biopsy with the conventional method, blue dye and/or radiotracer (B/R).
Results: In almost all cases, contrast-enhanced lymphatic vessels were clearly visualized US soon after the periareolar injection of SNZ, and SLN, into which lymphatic flow was draining, was easily identified. The identification rate of SLN was 98% (98/100) by SNZ and 100% (100/100) by B/R. The number of SLNs identified by SNZ (mean per patient, 1.52) was significantly (P &lt; 0.001) lower than that of those by B/R (2.22). Twenty-five patients had at least one metastasis in the SLNs identified by SNZ and/or B/R. In these patients, SLNs (n=39) identified by both SNZ and B/R showed a significantly (P &lt; 0.0001) higher positivity (74.4%) for metastases than those (n=19) identified by B/R alone (21.1%).
Conclusion: Identification of SLN by periareolar injection of SNZ followed by US is a technically easy method and the identification rate of SLN was as high as 98%, being comparable to the conventional B/R. SLNs detected by SNZ seem to represent the true SLNs which first receive lymphatic flow from the tumor among the SLNs detected by B/R.
Citation Format: Shimazu K, Ito T, Uji K, Miyake T, Motomura K, Noguchi S. Sentinel lymph node biopsy by contrast-enhanced ultrasonography with sonazoid in patients with breast cancer - Prospective multicenter study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-27.
Abstract P2-05-26: uPA/PAI-1 and adjuvant chemotherapy decision-making in early breast cancer
Authors: Deluche E , Venat-Bouvet L , Leobon S , Fermeaux V , Aubard Y , Saïdi N , Jammet I , Tubiana-Mathieu N 
Published: May 2019

Abstract
Background: Adjuvant chemotherapy decisions are relatively simple using clinicopathological parameters (Goldhirsch et al. 2007), some cases require the addition of biomarkers as in patients with node negative or micrometastatic (N0), grade II (GII) breast cancer. The objective of this study was to evaluate the impact of uPA/PAI-1 compared to classical criteria +/- KI67 in adjuvant treatment decision-making in this population.
Methods: This retrospective study included patients, treated from March 2008 to May 2016 in the Department of Medical Oncology at Limoges University Hospital (France). Ki67 and uPA/PAI-1 were analyzed on the initial specimen tumor. Optimal cut-off of Ki67 was defined at 20% (Coates et al. 2015). The positivity thresholds of uPA and PAI-1 were 3 ng/mg and 14 ng/mg respectively (Look et al. 2002). A positive uPA/PAI-1 level was defined as the elevation of at least one of these markers above the positivity threshold. All clinicopathological parameters were recorded prospectively.
Results: 2364 patients with breast cancer were screened. Among these patients, 256 N0, GII breast cancer patients were included with a median age of 62 years (32-87). Discordance between the two markers uPA/PAI-1 and KI67 was observed in 58% of tumors. Adding KI67 to the other classical clinicopathological parameters, 143 cases were defined as high risk versus 111 cases without KI67; low risk were defined in 113 cases versus 145 cases without KI67. Considering Ki67 status, the indication to perform adjuvant chemotherapy was increased by 29% compared to clinicopathological parameters. uPA/PAI-1 level was positive in these 143 high risk tumors in 93 cases and negative in 50 cases; in the 113 low risk tumors uPA/PAI-1 was positive in 72 cases and negative in 41 cases. uPA/PAI-1 increased indication to perform adjuvant chemotherapy by 15% compared to St Gallen criteria (including KI67) and by 49% compared to St Gallen criteria (excluding KI67). Using these two markers the final decision of chemotherapy by the multidisciplinary board was increased by 3% compared to St Gallen criteria (including KI67).
Conclusions: This study highlighted that uPA/PAI-1 and Ki67 assessment provides additional information for adjuvant chemotherapy decision-making. This study confirms the difficulty to assess the level of importance (weighting) of these biomarkers in adjuvant chemotherapy decision-making. The use of uPA/PAI-1 was feasible, cost-effective in N0, GII breast cancer's patients.
Citation Format: Deluche E, Venat-Bouvet L, Leobon S, Fermeaux V, Aubard Y, Saïdi N, Jammet I, Tubiana-Mathieu N. uPA/PAI-1 and adjuvant chemotherapy decision-making in early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-26.