tbuckley/cabot-search huggingface dataset:
Abstract 3503: Gilenya and Alimta interact to kill breast cancer cells
Authors: Jane L. Roberts, Seyedmehrad Tavallai, Andrew Poklepovic, Laurence Booth, Paul Dent
Journal: Cancer Research (2015)

Abstract The present studies sought to determine whether the anti-folate pemetrexed (Alimta) and the sphingosine-1-phosphate receptor modulator FTY720 (Fingolimod, Gilenya) interacted to kill tumor cells. FTY720 and pemetrexed interacted in a greater than additive fashion to kill breast, brain and colorectal cancer cells. Loss of p53 function weakly enhanced the toxicity of FTY720 whereas deletion of activated RAS strongly or expression of catalytically inactive AKT facilitated killing. In contrast, expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Indeed, combined drug exposure reduced the activity of AKT, p70 S6K and mTOR and activated JNK and p38 MAPK. Expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Treatment of cells with FTY720 and pemetrexed increased the numbers of autophagosomes in cells that correlated with increased LC3 processing and increased p62 levels. Knock down of ATG5 or Beclin1 suppressed autophagosome formation and cell killing by the drug combination. Sorafenib was previously shown to potently interact with pemetrexed to kill tumor cells. Sorafenib significantly enhanced the lethality of [FTY720 + pemetrexed] treatment in vitro and in vivo. Collectively our findings argue that pemetrexed, sorafenib and FTY720 could be a novel adjunct modality for breast cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Jane L. Roberts, Seyedmehrad Tavallai, Andrew Poklepovic, Laurence Booth, Paul Dent. Gilenya and Alimta interact to kill breast cancer 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 3503. doi:10.1158/1538-7445.AM2015-3503
Prostate-Specific Membrane Antigen PET/CT
Authors: André Henrique Dias, Mikkel Holm Vendelbo, Kirsten Bouchelouche
Journal: Clinical Nuclear Medicine (2016)

We describe 2 cases of Ga-PSMA PET/CT in prostate cancer patients. Both cases demonstrated symmetrical bilateral involvement of mediastinal and hilar lymph nodes besides findings in relation with prostatic disease. In both cases, endobronchial ultrasound-guided biopsy showed that the involvement of the thoracic lymph nodes was caused by nonnecrotic granulomas compatible with sarcoidosis. The cases demonstrated that increased Ga-PSMA uptake can be seen in lymph nodes with active sarcoidosis, with images mimicking those well known from FDG PET/CT. Because of these findings, granulomatous disease has to be included in the differential diagnostic evaluation of patients with Ga-PSMA-positive lymph nodes.
Abstract 4105: Cathepsin L inhibition reverts epithelial mesenchymal transition in prostate and breast cancer cells
Authors: Liza J. Burton, Bethany Smith, Manu Platt, Valerie Marah
Journal: Cancer Research (2015)

Abstract The Epithelial Mesenchymal Transition (EMT) is a key event in tumor migration and invasion processes whereby epithelial cells lose polarity together with cell-cell contacts associated with loss of epithelial markers such as E-cadherin and then undergo a dramatic remodeling of the cytoskeleton associated with expression of mesenchymal markers such as vimentin, as well as increased production of extracellular matrix (ECM)-degrading proteases. Snail is a gene that promotes epithelial mesenchymal transition (EMT) by using its zinc finger domains to bind to target genes that would otherwise stop EMT. Cathepsin L (Cat L) is a cysteine protease involved in cell invasion and has recently been associated with poor prognosis in Colon and Breast Cancer with Cat L being localized in the nucleus. We have shown previously that Snail-mediated EMT can be antagonized by muscadine grape skin extract (MSKE), a natural product rich in anthocyanin. In preliminary data we found that Snail, an inducer of EMT, could up-regulate Cat L activity and expression in breast cancer cells. We hypothesized that antagonizing Cat L activity would lead to mesenchymal epithelial transition (MET). We utilized breast and prostate EMT models to analyze Cat L activity using gelatin zymography and subsequently treated mesenchymal cells with 1μM, 5μM or 20μM Z-FY-CHO (Cat L specific inhibitor) or MSKE for 72 hours. We performed western blot analysis and immunofluorescence for EMT markers as well as invasion and migration assays. Our data indicates that mesenchymal MDA-MB-231 breast cancer cells showed higher Cat L expression and activity as compared to epithelial MCF-7 breast cancer cells. Interestingly, immunofluorescence analysis revealed cells displaying a higher snail expression have an increase in Cathepsin L activity and expression as well as Cat L being localized in the cytoplasm and nucleus. Additionally, mesenchymal breast (MDA-MB-231, MCF-7 cells overexpressing Snail) and prostate (ARCaP-M, ARCaP-E cells overexpressing Snail) cells displayed decreased expression of vimentin and Cat L expression and activity when treated with Z-FY-CHO or MSKE, while E-cadherin increased suggestive of MET. This was associated with decreased cell migration and invasion. We also show for the first time that treatment with MSKE or Z-FY-CHO changes the localization of Cat L from nuclear to cytoplasmic. Based on these results, the inhibition of Cat L could play a role in reverting EMT and preventing tumor progression. Citation Format: Liza J. Burton, Bethany Smith, Manu Platt, Valerie Marah. Cathepsin L inhibition reverts epithelial mesenchymal transition in prostate and breast cancer 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 4105. doi:10.1158/1538-7445.AM2015-4105
Abstract 1365: Visualizing the effect of BIBF1120 in lung cancer cells by imaging-massspectrometry (MS)
Authors: Daisuke Arai, Kenzo Soejima, Hiroyuki Yasuda, Kota Ishioka, Shizuko Kagawa, Junko Hamamoto, Katsuhiko Naoki, Katsura Emoto, Yuki Sugiura, Makoto Suematsu, Tomoko Betsuyaku
Journal: Cancer Research (2015)

Abstract Background: Angiogenesis plays an important role for tumor maintenance, progression, and metastasis. BIBF1120 is a multiple tyrosine kinase inhibitor, targeting VEGFR, FGFR and PDGFR, and is known as an anti-angiogenic agent. The mechanism by which anti-angiogenic agents suppress the growth of tumors is supposed to be induction of under-nutrition. However, no study has demonstrated the regional differences in the nutrition status of tumors treated by anti-angiogenic agents. Imaging MS is a novel technology that quantitatively visualizes the distribution of hundreds of metabolites in the selected area of tissues. Aim: The aim of this study is to evaluate the efficacy of BIBF1120 in lung cancer cells, and to examine whether BIBF1120 induces under-nutrition status in association with suppressed angiogenesis in xenograft models of lung cancer using Imaging MS. Method: We used lung cancer cell lines driven by several types of histology, PC9, H1975, H3122, A549, H69, and H520. The efficacy of BIBF1120 was evaluated by MTS assay and mouse xenograft model. We treated the xenografted mice with BIBF1120 or vehicle for 4 weeks and harvested xenograft tumors. Micro vessel density and percentage of apoptosis cells in the tumors was evaluated by immunohistochemistry using anti-Ki-67 antibody and anti-cleaved caspase 3 antibody, respectively. The effect of BIBF1120 on metabolic status in xenograft tumors was evaluated by imaging MS. Result: BIBF1120 inhibited the growth of all of the xenograft tumors tested, although it did not directly affect the proliferation rate of those cells in vitro. BIBF1120-treated tumors exhibited significantly lower micro vessel density compared to the vehicle-treated tumors (p&amp;lt;0.05), but BIBF1120 didn't increased the percentage of apoptosis cells. Imaging MS revealed that BIBF1120 treatment reduced 2-3 DPG (a maker of blood flow), glucose intake, and amount of ATP, whereas activated glycolysis via anaerobic metabolic pathway rather than oxidative phosphorylation in peripheral area of tumors. Conclusion: To our knowledge, this is the first report to demonstrate the effect of BIBF1120 on the nutrition status of tumor cells in a site-specific manner. Citation Format: Daisuke Arai, Kenzo Soejima, Hiroyuki Yasuda, Kota Ishioka, Shizuko Kagawa, Junko Hamamoto, Katsuhiko Naoki, Katsura Emoto, Yuki Sugiura, Makoto Suematsu, Tomoko Betsuyaku. Visualizing the effect of BIBF1120 in lung cancer cells by imaging-massspectrometry (MS). [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 1365. doi:10.1158/1538-7445.AM2015-1365
Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease
Authors: Fernando Bril, Diana Barb, Paola Portillo‐Sanchez, Diane Biernacki, Romina Lomonaco, Amitabh Suman, Michelle H. Weber, Jeffrey T. Budd, Maria E. Lupi, Kenneth Cusi
Journal: Hepatology (2016)

The cut-off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1 H-MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≥5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross-sectional study, 352 subjects were carefully characterized with the following studies: liver 1 H-MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∼1.5% and remained uniformly impaired (∼40%-45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∼6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = -0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content.IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∼6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL-C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132-1144).
Abstract 5306: Microparticles as novel prognostic markers in multiple myeloma
Authors: Sabna Rajeev Krishnan, Mary Bebawy, Ross Duncan Brown, Frederick Luk, Yiulam Kwan
Journal: Cancer Research (2015)

Abstract Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rates and confinement of the disease to bone marrow (BM). Relapse is a significant impediment in the clinical setting and the development of multidrug resistance (MDR) to therapy is the main cause of relapse. Currently, risk stratification to MM sub-groups and categorization of complete response to therapy are established on molecular and cytogenetic markers using bone marrow biopsies. We are exploring the clinical significance of plasma cell derived microparticles as a novel prognostic indicator in MM. Materials and Methods: We have analysed 79 de-identified MM patients and 24 normal subjects. Platelet free plasma was centrifuged and plasma cell derived MPs were identified and quantified by flow cytometry using Annexin V450, CD138 APC, anti-P-glycoprotein (P-gp)-FITC (17F9) in BD TruCount tubes. Platelet derived MPs were excluded from the analysis using CD41a-PE. All patient samples were compared to age-matched healthy volunteers. Western blot analysis was conducted on MP lysates probing for the presence of Lung-Resistance related Protein (LRP) and P-glycoprotein (P-gp). Morphology and the size of MP fraction from MM patients were investigated using scanning electron micrographs Results: The number of systemic MPs and CD138+MPs were found to be significantly higher in MM patient samples compared to the healthy volunteers. MDR markers (LRP &amp; P-gp) were expressed on systemic MPs from relapsing MM patients. MPs from patients were spherical in shape and had smooth surface consistent with those isolated from the MM cell line OPM2. Conclusions: There are elevated numbers of systemic MPs in all the 79 MM subjects (across all disease stages) compared to the healthy volunteers. The expressions of CD138 on MPs in the MM patients offer a sensitive assessment of disease progression and therapeutic outcome. Systemic MPs from MM patients carry a ‘snapshot’ of the less accessible bone marrow compartment and may provide a novel systemic ‘biosignature’ of MM progression and therapeutic outcome in the clinical setting. The MDR markers on systemic MPs may support dosage regimen and therapeutic decisions in MM clinical setting. Acknowledgements: This project has ethical approval from Sydney Local Health District Human Research Ethics Committee (CRGH)- EC00118 # HREC/11/CRGH/223 (CH62/6/2011/150). We would like to thank all the volunteers whom have contributed to this study. Citation Format: Sabna Rajeev Krishnan, Mary Bebawy, Ross Duncan Brown, Frederick Luk, Yiulam Kwan. Microparticles as novel prognostic markers in multiple myeloma. [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 5306. doi:10.1158/1538-7445.AM2015-5306
Vitamin D insufficiency in the first 6 months of infancy and challenge‐proven IgE‐mediated food allergy at 1 year of age: a case‐cohort study
Authors: J. Molloy, J. J. Koplin, K. J. Allen, M. L. K. Tang, F. Collier, J. B. Carlin, R. Saffery, D. Burgner, S. Ranganathan, T. Dwyer, A. C. Ward, M. Moreno‐Betancur, M. Clarke, A. L. Ponsonby, P. Vuillermin
Journal: Allergy (2017)

Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy.To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year.In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding.Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year.There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.
Abstract 4147: Synergistic effect of combined EGFR and Src inhibitor in colon cancer cell migration
Authors: Yi-Che Wu, Wan-Chen Wei, Wei-Ting Chao
Journal: Cancer Research (2015)

Abstract EGFR signaling plays the important role in cancer cell proliferation and cell migration. Cetuximab which is the antibody against EGFR was approved for colon cancer treatment. Recently, Src inhibitor, dasatinib has been demonstrated to improve drug sensitivity to cetuximab in KRAS mutant colorectal cancer cell growth. Src is a non-receptor tyrosine kinase which is necessary for full activation of EGFR and also functions in focal adhesion kinase activity in cell migration, therefore, the combination of cetuximab and dasatinib may has effect on colon cell migration. In this study, cetuximab and dasatinib were applied to SW480 colon cell which is KRAS mutant cell line. Cell viability and cell migration were analyzed, localization of Src and focal adhesion kinase (FAK) were observed by confocal microscopy. In the result, Combination of 5μM cetuximab and 40 nM dasatinib treatment resulted in synergistic effect on cell viability. However, when cetuximab combined with 25nM dasatinib was applied in trans-well migration assay, the synergistic inhibition on cell migration was observed. The immunofluorescence confocal microscopic image demonstrated cetuximab treatment induced phospho-Src accumulation on the cell membrane and colocalized with phospho-FAK. When the combination of 5μM cetuximab and 25 uM dasatinib were applied in the cell, the membrane accumulation of phospho-Src and Phospho-FAK were decreased. Taken together, cetuximab combined with dasatinib has synergistic efficacy in colon cancer cell proliferation, however, cetuximab combined with lower concentration of dasatinib (25nM) suppressed cell migration by inhibited FAK membrane localization through Src inactivation. Citation Format: Yi-Che Wu, Wan-Chen Wei, Wei-Ting Chao. Synergistic effect of combined EGFR and Src inhibitor in colon cancer cell migration. [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 4147. doi:10.1158/1538-7445.AM2015-4147
Abstract 1814: Effective auger electron radioimmunotherapy using modified anti-HER2 antibody with nuclear localizing signal
Authors: Huizi Li, Sumitaka Hasegawa, Tadashi Kamada, Tsuneo Saga
Journal: Cancer Research (2015)

Abstract Objective: Radioimmunotherapy has an advantage in treating tumors scattered in the body. Auger electrons have high cell killing effect because of its high LET, and the short range can prevent damages to normal tissue. However, to achieve higher therapeutic effect, it is desirable to deliver Auger electrons into nucleus and locate close to DNA. The use of nuclear localizing signal (NLS) has been proposed to transport Auger electron emitters into nucleus. To evaluate the cytotoxicity of nuclear localized Auger electron emitter, we performed in-vitro assay using 111In-labeled anti-HER2 antibody attached with NLS peptides to human breast cancer cell lines overexpressing HER2. Material and methods: Trastuzumab, a monoclonal antibody to HER2, was conjugated with CHX-A”-DTPA (DTPA) and derivatized with sulfosuccinimdyl-4-(N-maleimidomethyl) cyclohexane-1carboxylate (sulfo-SMCC) for reaction with synthetic 13-mer NLS peptides (CGYGPKKKRKVGG). 111In was labeled with either trastuzumab-DTPA or NLS-trastuzumab-DTPA, NLS-trastuzumab-DTPA-S carried approximately 4 NLS peptides per antibody and NLS-trastuzumab-DTPA-L carried 10. The radiochemical labeling of 111In-NLS-trastuzumab and 111In-trastuzumab was determined by HPLC. Human mammary epithelial cells HMEpC and two types of human breast cancer cells with low and high HER2 expression, MCF-7 and SKBR3, respectively, were employed for in-vitro study. Nuclear accumulation of 111In was measured in SKBR3 cells by subcellular fraction. Cell viability was evaluated with dye-based cell viability assays in all cell lines. DNA damages were examined with γ-H2AX immunohistochemistry in SKBR3 cells. Results: Nuclear uptake of 111In was 1.3-1.5-fold higher in SKBR3 cells treated with 111In-NLS-trastuzumab than 111In-trastuzumab and increased depending on the number of NLS peptides. Cell viability was significantly reduced with 111In-NLS-trastuzumab comparing 111In-trastuzumab in SKBR3 cells. Both of 111In-NLS-trastuzumab had little or no cytotoxicity on MCF-7 cells and HMEpC cells. SKBR3 cells treated with 111In-NLS-trastuzumab-L showed more γ-H2AX foci than 111In-trastuzumab. Conclusions: The cytotoxicity of 111In-NLS-trastuzumab was higher than that of 111In-trastuzumab by inducing more DNA damages in HER2-overexpressing human breast cancer cells. These data demonstrate that delivery of 111In into cell nucleus by anti-HER2 antibody harboring NLS is an effective strategy for targeted cell killing of the human cancer cells overexpressing HER2. Citation Format: Huizi Li, Sumitaka Hasegawa, Tadashi Kamada, Tsuneo Saga. Effective auger electron radioimmunotherapy using modified anti-HER2 antibody with nuclear localizing signal. [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 1814. doi:10.1158/1538-7445.AM2015-1814
Report on Response and Overall Survival of 128 Unselected, Consecutive AML Patients From the Austrian Azacitidine Registry (AAR) of the AGMT-Study Group
Authors: Lisa Pleyer, Reinhard Stauder, Sonja Burgstaller, Martin Schreder, Christoph Tinchon, Michael Pfeilstocker, Susanne Steinkirchner, Thomas Melchardt, Martina Mitrovic, Michael Girschikofsky, Alois Lang, Peter Krippl, Thamer Sliwa, Alexander Egle, Werner Linkesch, Michael A. Fridrik, Richard Greil
Journal: Blood (2011)