tbuckley/cabot-search huggingface dataset:
Abstract #43: Pomegranate juice extract and its main polyphenol, ellagic acid, up-regulate E-cadherin protein levels in COLO-357 pancreatic cancer cells
Authors: Melissa Rowland-Goldsmith, Krista Bledsoe, Jenna Tong, May Cao, Autumn Tocchi, Marissa Boardman, Christine Hughey, Carina Minardi, Nadia Reihanifam
Journal: Cancer Research (2009)

Our laboratory has been evaluating the effects of pomegranate juice extract (PJE) in inhibiting pancreatic cancer cell growth, the fourth leading cause of cancer death in the United States. There have been several published reports indicating that phytochemicals in fruits can reduce the risk of cancer due to their polyphenol anti-oxidant and anti-inflammatory effects. Pomegranate, from the tree  Punica granatum , possesses many polyphenols which makes it a valuable agent in cancer therapies. Previous reported studies using pomegranate juice (PJ) and pomegranate juice extract have shown promising results in suppressing colon, breast, lung, skin, and prostate cancer cell growth. Our lab has previously shown that PJ and PJE have anti-proliferative and pro-apoptotic effects in human COLO-357 pancreatic cancer cells. In addition, we observed that when treated with 10-25 µg/mL of PJE, cells become more adhesive, since they are harder to detach from the cell culture plate. It has been reported by other groups that low expression of Epithelial cadherin (E-cadherin) protein correlates with increased pancreatic cancer cell proliferation and metastasis. We hypothesized that treating human pancreatic cancer cells with low concentrations of PJE would increase cell adhesion by increasing E-cadherin protein levels. Another purpose of this project was to determine whether a particular polyphenol in commercial POMWonderful PJE was partially responsible for up-regulating E-cadherin. We characterized commercial POMWonderful pomegranate juice extracts by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and the most abundant polyphenols identified were: ellagic acid, galloylglucose, caffeolquinic acid, ellagic acid glucose, gallagic acid, punicalin, and punicalagin. We used ellagic acid (EA) for further studies since it is the only commercially available polyphenol identified. We also used EA because a recent publication showed that EA treatment in pancreatic cancer cells resulted in decreased cell proliferation and increased apoptosis. In our current study, we used the human COLO-357 pancreatic cancer cell-line to evaluate E-cadherin protein levels following PJE or EA treatments. We showed that PJE (10-25 ug/ml; 48 hours) resulted in a significant up-regulation of E-cadherin via immunoblots. We also demonstrated that EA (10-50 uMol/L; 48 hours) resulted in up-regulation of E-cadherin but not as dramatically as with PJE treatment. In conclusion, this data shows that PJE and its main polyphenol, EA, of the commercially available POMWonderful PJE helps restore pancreatic cancer cell adhesion, thereby serving as a potential suppressor of invasion and metastasis.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 43.
CSIG-15. SLFN5: A REPRESSOR OF INTERFERON-INDUCED SIGNALING THAT STIMULATES GLIOBLASTOMA CELL PROLIFERATION. SURVIVAL RESPONSES IN DIFFERENT XENOGRAFT GLIOBLASTOMA MOUSE MODELS
Authors: Frank D. Eckerdt, Mariafausta Fischietti, Craig Horbinski, C David James, Leonidas Platanias
Journal: Neuro-Oncology (2018)

The Schlafen (SLFN) family of proteins are involved with essential cellular functions in normal as well as tumor biology. In our previously published work (Oncogene 2017;36:6006–6019) we showed that high-level expression of SLFN5, an IFN-regulated member of the SLFN protein family, was correlated with shorter overall survival in glioblastoma (GBM) patients and that SLFN5 is a contributor to the aggressive biology of GBM in stimulating the proliferation, motility and invasiveness of GBM cells, as indicated by the results of in vitro assays. In that study we had also found that type-I IFN treatment triggers SLFN5 interaction with STAT1, and this suppresses STAT1-mediated gene transcription. Thus, SLFN5 is a repressor of IFN-gene transcription, suggesting the existence of a feedback loop that may contribute to the suppression of antitumor immune response. Here, we have examined the engraftment and xenograft growth effects of U87 SLFN5 KO cells. Wild-type (wt) and KO cells were intracranially injected in athymic nu/nu mice as well as NSG-SGM3 mice: the former are T-cell deficient whereas the latter are deficient in T-, B-, and NK cells. Athymic and NSG-SGM3 mice injected with KO cells lived significantly longer than mice injected with wt cells: all two-way comparisons yielded log-rank p-values of 0.011 or less. Interestingly, the survival of NSG-SGM3 mice injected with KO cells was significantly reduced relative to athymic nu/nu mice injected with the same cells: p = 0.027. This differential response raises the possibility of a potential immunosuppressive effect of SLFN5 involving NK and B-cells. Immunohistochemical analysis of intracranial xenograft tumors for KO effects on proliferation, apoptosis, and immune cell infiltrates is ongoing, and will be presented at the meeting.
AB0457 Clinical equivalence in efficacy between abp 501 and adalimumab in patients with moderate to severe rheumatoid arthritis: a tipping point sensitivity analysis
Authors: N. Zhang, H. Wang, E. Krishnan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> ABP 501 is the first approved biosimilar to adalimumab. Patient withdrawals from clinical trials can result in missing data, which may lead to loss of statistical power and bias of the treatment difference estimate. Therefore, it is critical to examine the potential effects of missing data and analyse the sensitivity of the results under various assumptions on the mechanism of missing data. <h3>Objectives</h3> To examine and confirm the robustness of the clinical similarity conclusion between ABP 501 and adalimumab reference product (RP) through tipping point sensitivity analyses on ACR20 at week 24, the primary endpoint of the phase 3 study in patients with rheumatic arthritis. <h3>Methods</h3> The primary analysis for this trial has been previously published. The proportions of patients achieving ACR20/50/70 responses with last observation carried forward imputation at weeks 2, 4, 8, 12, 18 and 24, were similar between ABP 501 and the RP over time. Tipping point sensitivity analyses were used to estimate the difference between ABP 501 and the RP with varying assumptions on the outcomes in patients who withdrew from the study early and those who completed the study. <h3>Results</h3> The table 1 displays the results of tipping point analyses on the primary endpoint of ACR20 at week 24. There were no scenarios in which the 90% confidence interval (CI) failed to rule out a 12% loss/increase in the ACR20 response. <h3>Conclusions</h3> The tipping point sensitivity analyses support the findings of the key efficacy analyses in the phase 3 RA study and confirm that the effects of missing data would not change the conclusion of clinical similarity between ABP 501 and the RP. <h3>Disclosure of Interest</h3> N. Zhang Shareholder of: Amgen Inc., Employee of: Amgen Inc., H. Wang Shareholder of: Amgen Inc., Employee of: Amgen Inc., E. Krishnan Shareholder of: Amgen Inc., Employee of: Amgen Inc.
CMET-45. CHECKPOINT BLOCKADE IMMUNOTHERAPIES FOR MELANOMA BRAIN METASTASES: IMPROVED SURVIVAL OUTCOMES IN A NATIONAL COHORT
Authors: J Iorgulescu, Maya Harary, Cheryl Zogg, Keith Ligon, Stephen Hodi, Ayal Aizer, David Reardon, Timothy Smith
Journal: Neuro-Oncology (2018)

The recent successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBM), the survival benefit of these novel therapies for MBM remains unknown. The characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010–2015 were evaluated using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan-Meier techniques. 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-yr OS to 14.1% (95CI:12.2–16.1) from 7.4% pre-approval (95CI:5.3–10.0, p<0.001). Post-approval, the proportion of MBM patients that received CBI rose from 10.5% in 2011 to 34.0% in 2015 (p<0.001). MBM patients were more likely to receive CBI if they were younger, more recently diagnosed, had fewer comorbidities, insured privately or through Medicare, diagnosed in New England, had brain-directed RT, or had involvement of other metastatic sites. Initial CBI in MBM patients displayed a 2.4x improved median and 4-yr OS of 12.4 mos (95CI:10.4–15.8; vs. 5.2 mos, 95CI:4.7–5.9, p<0.001) and 28.1% (95CI:22.1–34.4; vs. 11.1%, 95CI:9.3–13.1), which persisted in multivariable analyses (HR 0.12, 95CI:0.03–0.49, p=0.003). These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-yr OS of 56.4 mos (95CI:25.0-NR; vs. 7.7 mos, 95CI:6.7–8.7, p<0.001) and 51.5% (95CI:38.9–62.8; vs. 16.9%, 95CI:13.5–20.6). Using a large national cohort composed of a “real-life” MBM treatment population, we demonstrate the dramatic OS improvements associated with novel checkpoint blockade immunotherapies.
Immunosuppression Minimization Trials in Liver Transplantation: Can We Predict Humoral Response to Assess Eligibility?
Authors: Magdalena Meszaros, José Ursic‐bedoya, Stéphanie Faure, Georges‐philippe Pageaux
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To the Editor: We have read with great interest the article by Jucaud et al.1 reporting that de novo donor‐specific human leukocyte antigen (HLA) antibodies (dnDSA) development during immunosuppression (IS) withdrawal in liver transplantation (LT) was associated with acute rejection and prevented further attempts of IS withdrawal. Immunosuppression minimization and withdrawal trials are needed to obtain the best long‐term outcomes for liver transplant recipients. The main criteria for selecting appropriate liver transplant recipients for undergoing IS minimization and withdrawal consider the etiology of liver disease, time after transplant, liver tests, and histological assessment of liver graft.2 The paper reported by Jucaud et al. confirms that dnDSA are mostly produced against HLA class II antigens and introduces a possibly new criterion for IS withdrawal eligibility: positivity of dnDSA. The authors explain that one of the probable reasons for high prevalence of dnDSA in patients undergoing IS minimization and withdrawal (51.7% and 66.7%) was the high mismatch (MM) for seven HLA loci. Also, nonrandomized patients had a significantly higher median number of HLA class II MM (P = 0.009). It is now recognized that DSA are produced against HLA mismatches and that HLA antibodies recognize epitopes rather than antigens.3 Recently, Kubal et al.4 and our team,5 using two different approaches, HLAMatchmaker and the predicted indirectly recognizable human leukocyte antigen epitopes algorithm, reported that donor‐recipient class II HLA epitope MM is correlated with a high risk of dnDSA formation after LT. These results suggest that high epitope loads resulting from class II HLA epitope MM are correlated with dnDSA positivity in liver transplantation. By introducing additional data on HLA class II epitope mismatch related to donor‐recipient couple, the eligibility criteria for patient selection in IS withdrawal or early IS minimization studies may be refined, but further studies are required to confirm this hypothesis. Potential conflict of interest Nothing to report.
NIMG-46. LONGITUDINAL RESTING-STATE FUNCTIONAL CONNECTIVITY CONFIRMS MARIZOMIB (MRZ) CROSSES THE BLOOD BRAIN BARRIER (BBB) AND CORRELATES WITH HALLUCINATION SEVERITY IN RECURRENT GBM PATIENTS
Authors: David B Keator, Robert G. Bota, Steven L. Small, Daniela A Bota
Journal: Neuro-Oncology (2018)

MRZ is a second-generation, irreversible proteasome inhibitor currently in clinical trials for GBM. MRZ has ability to cross the BBB in animal models. CNS side-effects (including hallucinations and cerebellar ataxia) are both common adverse events. Here we report on the regional fMRI-derived functional connectivity changes associated with hallucination severity (graded using CTCAE 4.03) after MRZ treatment, administered at day 1, 8, and 15 every 28 days. Longitudinal resting-state fMRI whole-brain volumes (TR 2500ms, TE 20ms, flip angle = 71°, slice thickness = 3mm, gap = 0 mm, FOV 19.2 cm, matrix = 64 x 64, 51 slices, 120 volumes) were acquired on six participants at baseline (day 0) and days 1 and 15 of the treatment cycle. Preprocessing included: linear detrending, band-pass filtering, EPI signal from the white matter and CSF masks1; hand-drawn tumor masks; rigid-body realignment parameters; and motion and artifact scrubbing2 as implemented in the CONN toolbox3. Linear models were used to assess the correlations of hallucination severity and longitudinal functional connectivity changes in regions from the Harvard-Oxford atlas. After one day of treatment, we found hallucination severity was associated with decreased functional connectivity between the left lingual gyrus and both the left cerebellum (T(4)=-12.78, p<0.03 FDR) and left temporal cortex (T(4)=-9.56, p<0.04 FDR). After fifteen days, the association persisted but became more prominent between the bi-lateral temporal-occipital fusiform cortex and the bi-lateral cerebellum (left: T(4)=-20.20, p<0.005 FDR; right: T(4)=-17.75, p<0.008 FDR) along with decreased local efficiency in the left lateral occipital cortex (T(4)=-11.25, p<0.05 FDR). CONCLUSIONS: Our data suggest that MRZ induce changes in functional connectivity in selected brain areas, including the optic pathways and the cerebellum, confirming MRZ ability to cross the BBB in humans. Research to determine the relation between functional connectivity and response to MRZ are ongoing.
Abstract 16903: 22q11.2 Status Impacts on Perioperative Outcome in Tetralogy of Fallot
Authors: Laura Mercer-Rosa, Nelangi Pinto, Wei Yang, Ronn Tanel, Elizabeth Goldmuntz
Journal: Circulation (2012)

Background: Tetralogy of Fallot (TOF) is commonly associated with genetic syndromes. In particular, deletion of 22q11.2 (del22q) is seen in up to 17% of patients. The influence of del22q on surgical outcomes in TOF is not completely defined. Therefore, we sought to investigate the impact of del22q on perioperative outcomes in TOF. Methods: We conducted a retrospective review of patients with TOF who underwent complete surgical reconstruction at The Children's Hospital of Philadelphia from1995 to 2006. Inclusion criteria included confirmed diagnosis of TOF and known del22q genotype. Fisher's exact and Mann Whitney tests were used for categorical and continuous variables, respectively. Univariate and multivariate regression analyses were used to determine the association of deletion status with outcome. Results: We studied 208 subjects, 164 (79%) without, and 44 (20%) subjects with a del22q. There was no difference in sex, race, gestational age, age at diagnosis, admission weight, presence of extracardiac m...
EXTH-76. 1H AND HYPERPOLARIZED 13C MRS BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO TEMOZOLOMIDE THERAPY
Authors: Elavarasan Subramani, Chloe Najac, Georgios Batsios, Pavithra Viswanath, Marina Radoul, Anne Marie Gillespie, Russell Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2018)

The alkylating agent temozolomide (TMZ), previously reserved for treatment of glioblastoma, is now being considered for the treatment of low-grade glioma that are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Though the treatment of IDH1 mutant patients with TMZ improves survival, there is a need for metabolic imaging to help in assessing early response to therapy. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based biomarkers for detection of response to treatment. To address this, we examined the global metabolic alterations that occurred following TMZ treatment in a genetically engineered IDH1 mutant immortalized normal human astrocyte cell line (NHAIDHmut) using 1H and 13C MRS combined with chemometrics. Cells were treated either with the IC50 of TMZ (100 μM; N=5), or with DMSO (0.2%; N=5) for 72 hours. Then, metabolites were extracted from cells and 1H spectra acquired. Data were analyzed using SIMCA and the most significant metabolites contributing to class separation were identified using multivariate and univariate analyses. Alternatively, live cells were exposed to hyperpolarized 2-13C-pyruvate and dynamic sets of 13C-MRS spectra recorded to monitor the production of 5-13C-glutamate over time. 1H MRS showed that glutamine, glutamate, pyruvate, succinate, glucose, phosphocholine, isoleucine, valine, lysine, phenylalanine, NAD+/NADP+ and ATP/ADP/AMP were significantly higher in TMZ-treated cells as compared to controls. Accordingly, the tricarboxylic acid (TCA) cycle was identified as a significantly altered pathway following TMZ treatment. Consistent with this finding, dynamically probing the metabolism of hyperpolarized 2-13C-pyruvate revealed that build-up of 5-13C-glutamate, which is associated with flux to the TCA cycle, was significantly higher in TMZ-treated cells as compared to controls. Further studies are warranted for validation of our findings in other mutant IDH1 models. Nonetheless, our findings identify potential MRS-detectable early biomarkers of response to TMZ therapy in mutant IDH1 glioma.
COMP-10. ANTI-CORRELATED TGFβ AND ALTERNATIVE END-JOINING DNA REPAIR SIGNATURES ASSOCIATE WITH OUTCOME IN PRIMARY GBM
Authors: Mary Barcellos-Hoff, Ines Guix, Jade Moore, Miquel Angel Pujana, Luis Palomero, Qi Liu
Journal: Neuro-Oncology (2018)

Transforming growth factor β (TGFβ), which is distinctively overexpressed in glioblastoma (GBM) while undetectable in normal brain tissue, could underlie GBM intrinsic radioresistance by endorsing effective DNA damage responses. We showed that most (5/7) primary GBM explants respond to TGFβ and are radiosensitized by TGFβ inhibition, but a few were unresponsive in both assays (Neoplasia 18:795–805). To further examine the link between TGFβ and the DNA damage response we used microarray transcriptomes from 369 IDH wild-type GBM patients from The Cancer Genome Atlas Consortium (TCGA). Surprisingly, our study unveiled a very strong inverse correlation (Pearson’s correlation coefficient, PCC=-0.80; p<0.00001) between the single specimen gene set enrichment analysis (ssGSEA) using a signature for chronic TGFβ activity and one of alternative end-joining (alt-EJ), a backup pathway for DNA double-strand break repair that is error-prone and less effective. Notably, patients with the low TGFβ/high Alt-EJ profile exhibited significantly better progression-free survival (p<0.003) and overall survival (p<0.02). The same negative correlation of the TGFβ/Alt-EJ signature was evident in the GBM RNASeq TCGA data (PCC = -0.88, p<0.00001), which also showed that there was no correlation between TGFβ/alt-EJ and MGMT methylation status ssGSEA (p=0.8). These analyses are consistent with our hypothesis that high TGFβ in GBM opposes response to therapy and indicate that treatment with TGFβ inhibitors could potentially boost GBM therapeutic control. Moreover, since Alt-EJ depends on poly(ADP-ribose)polymerase 1 (PARP1), these data also suggest a novel mechanism by which to select patients that will be responsive to PARP inhibitors.
Abstract P073: Co-morbidities and Cardiac Associated Mortality in Smokers
Authors: Gregory L Kinney, Kendra A Young, Katherine Pratte, Elizabeth A Regan, Lindsey Duca, Barry Make, James Crapo, John Hokanson
Journal: Circulation (2017)

Background: Chronic Obstructive Pulmonary Disease (COPD) is a complex syndrome involving all aspects of the lungs which is strongly associated with cigarette smoking. Parenchymal destruction and remodeling are disease processes involving inflammatory pathways likely to have systemic vascular effects outside of the lungs. Indeed cardiovascular disease (CVD) is a leading cause of mortality in people affected by COPD and many co-morbid conditions are also associated with the disease. We explored CVD mortality in smokers considering aspects of COPD as well as co-morbidities in the longitudinal follow-up of the COPDGene study. Methods: The COPDGene study includes baseline and longitudinal assessment of mortality for 8,157 participants with (3,604) and without COPD (4,553) all of whom reported &gt;10 pack-years smoking exposure. Aspects of COPD including CT phenotyping and pulmonary function were combined using Principal Components Analysis (PCA), co-morbidities were combined using Latent Class Analysis (LCA) and cause specific mortality was assessed using study center reports, SSRI searches and single clinician adjudication. Cox Proportional Hazards models accounting for the effects of competing risks were used to assess the association between PCA factors and CVD mortality and PCA factors plus LCA classes and CVD mortality. Results: PCA analysis resulted in 5 factors describing emphysema, airway disease, gas trapping, BMI and its effect on CT measurement and hyperinflation and LCA analysis identified 7 classes of co-morbidities. CVD associated mortality occurred in 128 participants and competing causes of mortality occurred in 605. The PCA factor describing airway disease predicted CVD mortality in the PCA only model (HR 1.8, 95%C.I. 1.4-2.3,p&lt;0.0001), as well as in the LCA model (HR 1.7, 95% C.I. 1.3-2.2, p&lt;0.0001). LCA classes associated with CVD mortality include a class describing diabetes, high BP and high Cholesterol (HR 3.5, 95% C.I. 1.8-6.8, p=0.0003) and a class describing known CVD (HR 2.9, 95% C.I. 1.3-6.7, p=0.01). Conclusions: Co-morbidities of COPD represent independent predictors of CVD associated mortality in smokers accounting for pulmonary disease and competing mortality risks. Clustering of comorbidities using LCA is an approach that may be informative in complex diseases.
Abstract 14975: Thyroid and Glucocorticoid Hormones Promote Functional T-tubule Development in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes
Authors: Shan S Parikh, Daniel J Blackwell, Nieves Gomez-Hurtado, Michael Frisk, Lili Wang, Kyungsoo Kim, Christen P Dahl, Theis Tønnessen, Dmytro O Kryshtal, William E Louch, Bjorn C Knollmann
Journal: Circulation (2017)

Introduction: Human induced pluripotent stem cells (hiPSCs) are increasingly used for modeling heart disease and are under development for regeneration of the injured heart. Incomplete structural a...