bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 137: PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation
Authors: Dammann Kyle , Khare Vineeta , Lang Michaela , Claudel Thierry , Harpain Felix , Granofszky Nicolas , Evstatiev Rayko , Williams Jonathan M. , Pritchard D. Mark , Watson Alastair , Gasche Christoph 
Published: August 2015

Abstract
Background & Aims: P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling in inflammatory bowel diseases (IBD) including Crohn's disease (CD), ulcerative colitis (UC), and its role in colitis-associated carcinogenesis (CAC). Methods: PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry (IHC), immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single i.p. TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ were analyzed upon PAK1 overexpression and silencing. All data are mean±SD. Results: IHC revealed PAK1 expression increased from 2.8±1.6 in normal mucosa to 5.2±1.4 in CD, 6.0±1.7 in UC, and 8.8±1.0 in CAC. In UC, PAK1 activation increased at the luminal intestinal epithelial surface from 1.3±1.4 to 5.0±2.3. In primary colon epithelial cells, PAK1 was phosphorylated upon treatment with IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 from 4.3±1.0 to 9.9±0.1 in intestinal villi, which co-localized with NF-κB activation. Indeed, p65 nuclear translocation downstream of TNFα was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear p65 translocation, and increased NF-κB transactivation four fold, all of which were impeded upon kinase-dead PAK1. Also PAK1 overexpression downregulated PPARγ mRNA levels from 1 to 0.4±0.1 and mesalamine recovered PPARγ to 0.8±0.04 through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB transactivation from 1 to 0.1±0.02, which was recovered upon the PPARγ antagonist BADGE to 0.5±0.1. Conclusions: Altogether these data demonstrate that PAK1 overexpression and activation in IBD and CAC promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.
Citation Format: Kyle Dammann, Vineeta Khare, Michaela Lang, Thierry Claudel, Felix Harpain, Nicolas Granofszky, Rayko Evstatiev, Jonathan M. Williams, D. Mark Pritchard, Alastair Watson, Christoph Gasche. PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 137. doi:10.1158/1538-7445.AM2015-137
Abstract 1567: A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients
Authors: Mahalingam Devalingam , Washburn William K. , Halff Glenn , Chelis Leonidas , Kakolyris Stylianos , Vradelis Stylianos , Grigorieva Julia , Oliveira Carlos , Roder Heinrich , Roder Joanna 
Published: August 2015

Abstract
Improved screening protocols (SP) for patients at high risk of developing HCC could lead to improved patient outcome and possibly cure if detected early. The current SPs, ultrasound with the possible addition of alphafetoprotein (AFP) measurement, suffer from insufficient sensitivity and specificity, and less than 30% of patients are diagnosed early enough to be suitable candidates for resection or transplantation. An easy to use biomarker for the early detection of HCC is clearly needed.
We used mass spectrometry analysis of serum samples combined with specialized deep learning techniques to train and validate such a test. The development cohort consisted of patients undergoing transplant or resection for HCC (N = 52; median MELD = 14), and patients with advanced cirrhosis undergoing liver transplant (N = 53; median MELD = 25). Underlying cause of liver disease was 51% hepatitis C infection. The validation cohort consisted of patients with advanced HCC (N = 103; 70/26/7 Child-Pugh A/B/C) and liver disease but no HCC (N = 77; 68/7/2 Child-Pugh A/B/C), with 68% of patients having hepatitis B infection (HBV). The classifier was trained especially to avoid confounding by liver function.
The resulting test showed a sensitivity/specificity of 73%/95% in cross validation in the development set overall. In the subset of T1 patients (or lesion size &lt;2 cm) accuracy was 72% (75%). Performance was good across all represented causes of liver disease. The test was shown not to be confounded by liver function by classifying healthy patients (N = 17) as ‘no cancer’. In the validation set the performance was 89%/73%, with 91%/78% in the HBV subgroup and 90%/75% in the Child-Pugh A subgroup.
The developed test shows promise in the early detection of HCC as a screening tool in high risk patients independent of the cause of underlying liver disease. While further validation will be necessary to conclusively prove its clinical validity, we believe such a test could substantially improve early detection of HCC.
Citation Format: Devalingam Mahalingam, William K. Washburn, Glenn Halff, Leonidas Chelis, Stylianos Kakolyris, Stylianos Vradelis, Julia Grigorieva, Carlos Oliveira, Heinrich Roder, Joanna Roder. A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1567. doi:10.1158/1538-7445.AM2015-1567
Abstract 1573: miR-Test: a blood test for lung cancer early detection
Authors: Montani Francesca , Marzi Matteo Jacopo , Dezi Fabio , Dama Elisa , Carletti Rose Mary , Bonizzi Giuseppina , Bertolotti Raffaella , Bellomi Massimo , Rampinelli Cristiano , Maisonneuve Patrick , Spaggiari Lorenzo , Veronesi Giulia , Nicassio Francesco , Di Fiore Pier Paolo , Bianchi Fabrizio 
Published: August 2015

Abstract
Background:
Lung cancer is the leading cause of cancer death worldwide. As lung cancer is asymptomatic in its early stages, the majority of patients are diagnosed with advanced disease, when the tumor is unresectable. Consequently, the survival rate is very low: 15% at 5 years. It is vital, therefore, that screening programs and novel diagnostic tools are developed, which will increase the detection of lung cancer in its early stages (stage I-II), when the tumor is still curable, to reduce lung cancer mortality. Recently, we described a serum microRNA signature diagnostic for asymptomatic, early stage, lung cancer. The availability of reliable biomarkers to identify high-risk individuals might help to reduce the size of the target population for LDCT-based programs, thereby reducing costs and probably increasing compliance
Methods:
We performed a large-scale validation study of a miRNA blood test based on our signature (the miR-Test) in a population of high-risk individuals (N = 1115) enrolled in the lung cancer screening program COSMOS (Continuous Observation of SMOking Subjects), and other 74 lung cancer patients diagnosed outside of screening.
Results:
The miR-Test showed overall accuracy, specificity and sensitivity of 75%, 78%, and 75%, respectively, with an AUC of 0.85. The test appears to have a dual origin: the first from epithelial cells (the epithelial-like component); the second from cells of hematopoietic origin (the inflammatory-like component). Of note, we found that both components are needed to maintain a good performance of the miR-Test.
Conclusions:
The relatively high sensitivity of the miR-Test in detecting asymptomatic lung cancer and its high negative predictive value (NPV &gt; 99%), confirm the effectiveness of the test, both interms of its ability to identify asymptomatic lung cancer patients and to reduce significantly unnecessary CTs on healthy individuals.
Citation Format: Francesca Montani, Matteo Jacopo Marzi, Fabio Dezi, Elisa Dama, Rose Mary Carletti, Giuseppina Bonizzi, Raffaella Bertolotti, Massimo Bellomi, Cristiano Rampinelli, Patrick Maisonneuve, Lorenzo Spaggiari, Giulia Veronesi, Francesco Nicassio, Pier Paolo Di Fiore, Fabrizio Bianchi. miR-Test: a blood test for lung cancer early detection. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1573. doi:10.1158/1538-7445.AM2015-1573
Abstract 1629: Prednisone versus dexamethasone acute toxicity and cumulative doses variations in childhood acute lymphoblastic leukemia
Authors: Marcoux Sophie , Chapdelaine Aurélie , Robaey Philippe , Sinnett Daniel , Krajinovic Maja , Laverdière Caroline 
Published: August 2015

Abstract
INTRODUCTION
Glucocorticoids (GC) are the main components of childhood acute lymphoblastic leukemia (ALL) treatment; in the past decades, there were numerous attempts at finding whether prednisone or dexamethasone is the best drug.
EXPERIMENTAL PROCEDURE
A retrospective study of patients (n = 119) treated according to Dana-Farber Cancer Institute (DFCI)-ALL treatment protocols 91-01 and 95-01 was done. Medical charts were reviewed and type and doses of glucocorticoids (GC) received were recorded. Bone and psychiatric symptoms, as well as all anthropomorphic data were also recorded.
For each patient, a total theoretical dose was calculated according to the initial risk of relapse stratification, treatment protocol indications and assigned arms. Cumulative GC doses actually received were compared to theoretical doses in the form of a dose deviation in% ((theoretical dose - actual dose) / theoretical dose * 100).
SUMMARY OF DATA
Results indicate that despite an adequate correlation between planned and administered GC doses for most patients, patients treated with dexamethasone were found to have significantly more GC dose deviations than those treated with prednisone (p &lt; 0.001). Findings also indicate that bone toxicity (p = 0.02), but not psychiatric toxicity, is associated with GC dose deviations.
CONCLUSIONS
Despite representing the current standard in clinical studies, using only different treatment arms or different treatment protocols may lead to significant interpretation caveats if doses actually received are not controlled for. This is of importance especially for drugs likely to induce very severe side-effects requiring dose modification, as it is the case for GC and acute bone toxicity.
Citation Format: Sophie Marcoux, Aurélie Chapdelaine, Philippe Robaey, Daniel Sinnett, Maja Krajinovic, Caroline Laverdière. Prednisone versus dexamethasone acute toxicity and cumulative doses variations in childhood acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1629. doi:10.1158/1538-7445.AM2015-1629
Abstract 1679: Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian cancer
Authors: Liu Chao Lien , Mao Tsui Lien 
Published: August 2015

Abstract
Ovarian carcinoma is the most crucial and difficult problem for therapeutic treatment in gynecological malignancies, which requires great efforts for an effective solution. Molecular studies have shown that chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 and its receptor CXCR4 are the key determinants of tumor initiation, progression and metastasis in ovarian carcinoma. It is also believed that blocking CXCR4-CXCL12 pathway plays potential roles in treating ovarian cancer patients. Recent studies also showed that the cytotoxic function of gamma delta (γ/δ) T lymphocytes could efficiently kill ovarian CSCs (cancer stem cells) and present a promising immunotherapy for ovarian cancer. To investigate how the CXCL12/CXCR4 pathway is involved in the regulation of ovarian cancer. We eliminated the expression of CXCR4 in different ovarian cancer cell lines using CXCR4 antagonist (e.g., AMD3100) and CXCR4 shRNA silencing to prevent the CXCR4/CXCL12 axis interaction. Besides, up to 78% of γ/δ T cells was expanded in-vitro using aminobisphosphonates plus low-dose interleukin-2 for the therapeutic investigating. The therapeutic effects following different treatments were measured. First, our results showed that blocking of Cxcr4/Cxcl12 axis by AMD3100 reduced around 37% on cell survival rate. Similar results were also observed in the CXCR4-shRNA silencing ovarian cancer cells. Additionally, the higher CXCR4-expressed cells were highly proliferation after CXCL12 stimulating compared to the CXCR4 non-expressed cells. Next, cancer cells treated with the exogenous activated γ/δ T cells showed a reduction of 35% on cell survival rate. Finally, the combined treatment strategy using AMD3100 plus γ/δ-T cells showed the most significant therapeutic effects in the high-grade ovarian cancer cells, and the cell survival rate was reduced almost to 50% after the cell cytotoxic assay. We therefore conclude that the limitation of CXCL12/CXCR4 activities combined with the γ/δ T cell cytotoxicity is a potent immunotherapy for treating ovarian cancer and would served as a promising new strategies for clinical translation.
Citation Format: Chao Lien Liu, Tsui Lien Mao. Immunotherapeutic strategies targeting CXCR4 axis plus γ/δ T cells in treating ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1679. doi:10.1158/1538-7445.AM2015-1679
Abstract 1716: Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation
Authors: Zhang Yong-Wei , Nasto Rochelle E. , Varghese Rency , Jablonski Sandra A. , Serebriiskii Ilya G. , Surana Rishi , Calvert Valerie S. , Bebu Ionut , Murray Joseph , Jin Lu , Johnson Michael , Riggins Rebecca , Ressom Habtom , Petricoin III Emmanuel , Clarke Robert , Golemis Erica A. , Weiner Louis M. 
Published: August 2015

Abstract
Approximately 70% of newly diagnosed breast cancers express high levels of estrogen receptor alpha (ERα). However, de novo and acquired drug resistance to anti-estrogen agents limit the treatment of such patients, requiring the use of cytotoxic chemotherapy; many such patients have a poor prognosis. Therefore, resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen-receptor positive breast cancer. To address this challenge, a system biological approach by screening a library of siRNAs targeting an estrogen receptor- and aromatase-centered network, was used and identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells, and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent estrogen-receptor positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mTOR inhibitors in estrogen-independent cells but not estrogen-dependent cells. Phosphoproteomic profiles (results from reverse phase protein array, RPPA) under basal conditions and following TOB1 depletion identified significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. The translational significance of this new molecular mechanism of estrogen independence in human breast cancer will be fully determined when TOB1 inhibitors are developed to enable in vivo validation studies. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, which have potential translational significance for the management of patients with estrogen receptor-positive breast cancers.
Citation Format: Yong-Wei Zhang, Rochelle E. Nasto, Rency Varghese, Sandra A. Jablonski, Ilya G. Serebriiskii, Rishi Surana, Valerie S. Calvert, Ionut Bebu, Joseph Murray, Lu Jin, Michael Johnson, Rebecca Riggins, Habtom Ressom, Emmanuel Petricoin III, Robert Clarke, Erica A. Golemis, Louis M. Weiner. Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1716. doi:10.1158/1538-7445.AM2015-1716
Abstract 1768: Chloroquine potentiates carfilzomib but not bortezomib effects on myeloma cells
Authors: Misund Kristine , Baranowska Katarzyna Anna , Holien Toril , Starheim Kristian , Johansson Ida , Buene Glenn , Waage Anders , Bjørkøy Geir , Sundan Anders 
Published: August 2015

Abstract
Proteasomal inhibition has proven good clinical effect in Multiple Myeloma; however, some patients are resistant to treatment and most patients acquire resistance during the disease course. It is well known that cells degrade proteins by two distinct but interconnected pathways; one is protein degradation by proteasomes, which may be clinically targeted by proteasome inhibitors, the other is by formation of autophagosomes and lysosomal degradation, which can be inhibited by hydroxychloroquine (HCQ). Assuming that the two arms of protein degradation may compensate for each other, there is a rationale to simultaneously target both arms. We tested the combined effects of HCQ and the reversible proteasome inhibitor bortezomib or the irreversible inhibitor carfilzomib on myeloma cell lines and primary cells. As expected, HCQ potentiated carfilzomib-induced myeloma cell death, but surprisingly, HCQ had little or no effect on bortezomib activity. We also found that HCQ potentiated the effect of the irreversible proteasome inhibitor oprozomib, but not the effect of the reversible inhibitor ixazomib. Thus, the sensitivity towards the irreversible proteasome inhibitors carfilzomib or oprozomib is to a larger extent affected by the autophagic system than the reversible inhibitors bortezomib and ixazomib. In conclusion, we here suggest that in attempts to increase the clinical efficacy of proteasome inhibitors, inhibitors of autophagy and lysosomal degradation such as HCQ should be combined with an irreversible proteasome inhibitor such as carfilzomib, and not with bortezomib.
Citation Format: Kristine Misund, Katarzyna Anna Baranowska, Toril Holien, Kristian Starheim, Ida Johansson, Glenn Buene, Anders Waage, Geir Bjørkøy, Anders Sundan. Chloroquine potentiates carfilzomib but not bortezomib effects on myeloma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2015-1768
Abstract 1840: Metabolomic profiling of gastrointestinal stromal tumor (GIST) T1 cell lines in response to imatinib therapy
Authors: Marks Vered , Tiesi Gregory , Paz Mejia Ana , Trent Jonathan , Walls Jamie , Livingstone Alan , Yakoub Danny 
Published: August 2015

Abstract
Background: There is a growing need for novel drugs to treat drug resistant GIST. The aim of this study was to evaluate chronological metabolic changes in GIST cells treated with imatinib mesylate.
Methods: Human GIST T1 cells were incubated with imatinib 0.5 mM. Metabolomic profiling was performed in extracted cell pellets at 12, 24 and 48 hours, after viability and cell counting was done, and compared with controls via acquisition of 1H-NMR spectra using a 500MHz spectrometer equipped with a 5mm TCI 500S2 H-C/N-D-05 Z cryoprobe head at 298 K. Standard, one-dimensional NOESYpr1D pre-saturation pulse program was used. Spectra were further processed in an NMR suite processor; Partial Least Squares Discriminant Analysis (PLS-DA) model was used for characterization of chronological biochemical differences.
Results:
By 48 hours of exposure of cells to imatinib, glucose initially increased then significantly decreased with gradual decrease of lactate production and minimal changes in pyruvate and succinate denoting shifting from cytosolic to mitochondrial glycolysis, this was echoed with consumption of glutamine and glutamate. Glutathione and cell membrane phospholipids as phosphocholine gradually decreased by a factor of 1.6 for each, suggesting inhibited growth and invasiveness. Aspartate, myo-inositol, glycerophosphocholine and taurine gradually increased by a factor of 1.6, 1.7, 2.6 and 1.3, respectively. Tyrosine, valine and leucine showed minimal changes. Cell viability was directly correlated to changes in choline, creatine phosphate, myo-inositol and taurine (Pearson's R &gt;0.65). PLS-DA model suggested that changes in myoinositol, glycerophosphocholine, glutamate, aspartate, phosphcholine and glutathione were the metabolites mostly influencing the differential chronological global metabolic profiles of the cells with continued exposure to imatinib (R2X = 0.76, R2Y = 0.60, Q2(cum) = 0.20).
Conclusion:
Metabolomic profiling of GIST cells exposed to signal transduction modulators supplements molecular findings and provides further mechanistic insights into longitudinal changes of the mitochondrial and glycolytic pathways of oncogenesis, it can potentially provide novel as well as complementary therapeutic targets.
Citation Format: Vered Marks, Gregory Tiesi, Ana Paz Mejia, Jonathan Trent, Jamie Walls, Alan Livingstone, Danny Yakoub. Metabolomic profiling of gastrointestinal stromal tumor (GIST) T1 cell lines in response to imatinib therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1840. doi:10.1158/1538-7445.AM2015-1840