tbuckley/cabot-search huggingface dataset:
Abstract LB-011: Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro
Authors: Fernando Abaitua, Justyna Przystal, Amin Hajitou, Nelofer Syed
Journal: Cancer Research (2015)

Abstract Patients with Gliobastoma Multiforme (GBM) have an extremely poor overall survival rate. Novel molecular targeted therapies have failed to provide further improvements in these rates and as such the standard of care for GBM patients remains unchanged, consisting of radical surgery followed by chemo and radiotherapy. In light of this, novel therapeutic approaches have to be tested in combination with current protocols for their efficacy. We have previously demonstrated the metabolic dependency of ∼30% of de novo GBM to extracellular arginine. Using ADI-PEG20 to deplete arginine, we showed a marked reduction in the proliferation of primary GBM explants that exhibited methylation in their ASS1 gene, the rate-limiting enzyme in the arginine biosynthetic pathway. We have validated these findings in an animal model where we have demonstrated that ADI-PEG20 treatment induces a profound delay in the growth of ASS1-ve intracranial human GBM tumors in mice. In cell culture models, we show that ADI-PEG20 has comparable cell growth inhibition efficiencies as conventional chemotherapies namely temozolomide, lomustine and chloroquine. Moreover, these agents exhibited inhibitory effects on proliferation in hypoxic conditions (1% O2) representing activity in a more physiological environment. Importantly, combination with ADI-PEG20 did not reduce efficiency of these conventional drugs. Although no synergistic effects of ADI-PEG20 with these chemotherapeutic agents was observed, synergy was detected in combination with irradiation. Here, we showed the ADI-PEG20 radio-sensitized GBM cell lines to photon irradiation regardless of their ASS1 methylation status: In clonogenic assays, there was a 50% enhanced decrease in colony formation with pre-treatment of ADI-PEG20 and subsequent photon irradiation when compared to irradiation alone. These results suggest arginine deprivation therapy as a novel therapeutic strategy for ASS1-ve GBM. Moreover, we show that when combined with irradiation, ADI-PEG20 can be used to treat GBM irrespective of their ASS1 status. Citation Format: Fernando Abaitua, Justyna Przystal, Amin Hajitou, Nelofer Syed. Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro. [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 LB-011. doi:10.1158/1538-7445.AM2015-LB-011
Stomatitis incidence and its relationship with efficacy: A meta-analysis of everolimus clinical studies.
Authors: Hope S. Rugo, James C. Yao, Marianne Pavel, Alain Ravaud, David Neal Franz, Tanya Taran, Jorge Gallo, Nicolas Rouyrre, Oezlem Anak, Robert J. Motzer
Journal: Journal of Clinical Oncology (2014)

151 Background: The most common adverse event (AE) with everolimus (EVE) is stomatitis. This meta-analysis evaluated the incidence, severity, and possible impact of stomatitis on efficacy in patients (pts) with cancer or tuberous sclerosis complex (TSC) who received EVE. Methods: Stomatitis events from 7 randomized, double-blind, phase 3 EVE studies included: RECORD-1 (RCC), RADIANT-2 (NET), RADIANT-3 (pNET), BOLERO-2 (HR+/HER2- breast cancer [BC]), BOLERO-3 (HER2 + BC), and EXIST-1 and -2 (TSC). Time to first stomatitis occurrence and recurrence were analyzed using Kaplan-Meier (KM) methods. Stratified Cox regression analysis adjusted for baseline prognostic factors and corrected for confounding effect of duration of exposure was used to analyze association between stomatitis occurrence (≤ 8 wks of EVE start) and PFS in pts with cancer and response rate in pts with TSC. Results: This evaluation included EVE-treated pts with cancer (n = 1,455) and TSC (n = 157). Pts with cancer had stomatitis incidence of 66.9%, which occurred early, median 0.82 mo (95% CI, 0.7-1.0; 2-mo KM estimate 60.8%). 8.6% were grade 3/4 events. 1.7% of pts discontinued due to stomatitis. Stomatitis recurred in 40% of pts and appeared gradually. In pts with TSC similar results were observed. In EVE-treated pts, development of stomatitis was associated with longer PFS (corrected HR [95% CI]) in BOLERO-2 (0.78 [0.62-1.00]) and RADIANT-3 (0.70 [0.48-1.01]), and similar trend was observed in RECORD-1 (0.90 [0.66-1.22]) and RADIANT-2 (0.87 [0.61-1.22]), but not in BOLERO-3. In TSC, probably due to few pts, relationship between stomatitis and response was not conclusive. In all trials, pts on EVE had longer PFS vs placebo irrespective of stomatitis incidence. Conclusions: Stomatitis is observed frequently in initial wks of EVE therapy. Most AEs were grade 1/2 and manageable, rarely led to pt discontinuation. Stomatitis recurred in &lt; 50% of pts. EVE-treated pts with cancer who had stomatitis achieved stable benefit similar to overall population, suggesting that continuing EVE is helpful. The importance of prophylactic measures in reducing EVE-induced stomatitis incidence and improving its management is being determined by ongoing studies.
Safety and Efficacy of Marqibo (Vincristine Sulfate Liposomes Injection, OPTISOME™) in for the Treatment of Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL).
Authors: Deborah A. Thomas, Hagop M. Kantarjian, Wendy Stock, Leonard Heffner, Alexandra Tredinnick, Baio Lu, Gavin S. Choy, Steven R. Deitcher, Susan M. O’Brien
Journal: Blood (2007)
Prognostic Impact of Minimal Residual Disease (MRD) in Children Is Different in B or T Lineage Acute Lymphoblastic Leukemia: Results of Trial AIEOP-BFM ALL 2000.
Authors: Martin Schrappe, Carmelo Rizzari, Georg Mann, Anja Möricke, Maria Grazia Valsecchi, Martin Zimmermann, Claus R. Bartram, Renate Panzer-Grümayer, André Schrauder, Gianni Cazzaniga, Thomas Flohr, Rosanna Parasole, Alfred Reiter, Wolf-Dieter Ludwig, Luca Lo Nigro, Giuseppe Basso, Giulio De Rossi, Elena Barisone, Felix Niggli, Helmut Gadner, Valentino Conter
Journal: Blood (2007)
The Serine/Threonine Kinase Pim-2 Is a Novel Anti-Apoptotic Mediator in Myeloma Cells.
Authors: Jin Asano, Masahiro Abe, Shiro Fujii, Osamu Tanaka, Ai Mihara, Shingen Nakamura, Kazuhiro Miki, Kumiko Kagawa, Kyoko Takeuchi, Kenichiro Yata, Toshihiro Hashimoto, Shuji Ozaki, Masahiro Hiasa, Toshio Matsumoto
Journal: Blood (2007)
Abstract 5108: Oscillatory calcium signal drives melanoma invasion and metastasis
Authors: Jianwei Sun, Fujian Lu, Huifang He, Heping Cheng, Shengyu Yang
Journal: Cancer Research (2015)

Abstract Ca2+ signaling has been increasingly implicated in cancer invasion and metastasis, and yet the underlying mechanisms remained largely unknown. Here, we report that STIM1- and Orai1- mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca2+ oscillation signals facilitate invadopodial precursor assembly by activating Pyk2 phosphorylation at tyrosine 402, which directly binds to and activates Src to promote invadopoium assembly. Disruption of Ca2+ oscillations inhibited invadopodium assembly. Futhermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodium. Mechanistically, Orai1 blockade inhibits the recycling of MT1-MMP to the plasma membrane and entraps MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca2+ -mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca2+ signals during melanoma invasion and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Jianwei Sun, Fujian Lu, Huifang He, Heping Cheng, Shengyu Yang. Oscillatory calcium signal drives melanoma invasion and metastasis. [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 5108. doi:10.1158/1538-7445.AM2015-5108
Abstract LB-240: SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer
Authors: Andreas Papadakis*, Chong Sun*, Theo Knijnenburg, Yibo Xue, Wipawadee Grernrum, Michael Hölzel, Wouter Nijkamp, Lodewyk Wessels, Roderick Beijersbergen, Rene Bernards#, Sidong Huang#
Journal: Cancer Research (2015)

Abstract Recurrent inactivating mutations in components of SWI/SNF chromatin-remodelling complexes have been identified across cancer types, supporting their roles as tumour suppressors in modulating oncogenic signalling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCE1 knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signalling and suggest targeted treatment options for SMARCE1 deficient tumours. ACKNOWLEDGEMENTS: *Equal contribution. #Corresponding authors. This work was supported by grants from Canadian Institutes of Health Research (CIHR) grant MOP-130540 (S.H.), Canada Research Chair (CRC), the European Research Council (ERC), the Dutch Cancer Society (KWF), the EU COLTHERES project and grants by the Netherlands Organization for Scientific Research (NWO) to the Cancer Genomics Center Netherlands (CGC.NL). Citation Format: Andreas Papadakis*, Chong Sun*, Theo Knijnenburg, Yibo Xue, Wipawadee Grernrum, Michael Hölzel, Wouter Nijkamp, Lodewyk Wessels, Roderick Beijersbergen, Rene Bernards#, Sidong Huang#. SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung 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 LB-240. doi:10.1158/1538-7445.AM2015-LB-240
PWE-019 Expression of plasminogen activator inhibitor 1 in the stomach is linked to increased food intake and obesity
Authors: S Kenny, S Lyons, N Vlatkovic, R Dimaline, A Varro, G J Dockray
Journal: Gut (2010)

OBJECTIVE: To determine if participation of the spouse of patients with rheumatoid arthritis in cognitive-behavioral oriented self-management training aimed at improving disease related cognitions and coping with pain has additional benefits for the patients. METHODS: A total of 59 couples were randomly assigned to 2 conditions. In the experimental condition the couples participated in a group program aimed at restructuring disease related cognitions and decreasing passive coping. In the control condition, only the patient participated. Disease status, self-reported physical and psychological functioning, coping, disease related cognitions, and marriage characteristics were assessed prior to the intervention and 2 weeks and 6 months postintervention. A general linear model with repeated measures was used to test for differences between conditions. RESULTS: In both conditions, similar positive changes in disease activity, cognitions, coping, and physical and psychological functioning were observed. Patients reported a decrease in potential support. There were no differences between conditions. However, at the followup assessment patients in the experimental condition reported more improvement of disease related communication with their spouse. CONCLUSION: No evidence was found for additional beneficial effects of spouse participation in the cognitive-behavioral oriented self-management group treatment.
109. Therapeutic Efficacy and Safety Profile of EGFR-Targeted Oncolytic Ad Nanocomplex in Orthotopic Lung Tumor Model
Authors: A-Rum Yoon, Dayananda Kasala, Yan Li, Jinwoo Hong, Wonsig Lee, Soo-Jung Jung, Chae-Ok Yun
Journal: Molecular Therapy (2016)

Adenovirus (Ad)-mediated cancer gene therapy has been proposed as a promising alternative to conventional therapy for cancer. However, success of systemically administered naked Ad has been limited due to the immunogenicity of Ad and the induction of hepatotoxicity caused by Ad's native tropism. In this study, we synthesized an epidermal growth factor receptor (EGFR)-specific therapeutic antibody (ErbB)-conjugated and PEGylated PAMAM dendrimer (PPE) for complexation with Ad. Transduction of Ad was inhibited by complexation with PEGylated PAMAM (PP) dendrimer due to steric hindrance. However, PPE-complexedAd selectively internalized into EGFR-positive cells with greater efficacy than either naked Ad or Ad complexed with PP. Systemically administered PPE-complexed oncolytic Ad elicited significantly reduced immunogenicity, nonspecific liver sequestration, and hepatotoxicity than naked Ad. Furthermore, PPE-complexed oncolytic Ad demonstrated prolonged blood retention time, enhanced intratumoral accumulation of Ad, and potent therapeutic efficacy in EGFR-positive orthotopic lung tumors in comparison with naked Ad. We conclude that ErbB-conjugated and PEGylated PAMAM dendrimer can efficiently maskAd's capsid and retarget oncolytic Ad to be efficiently internalized into EGFR-positive tumor while attenuating toxicity induced by systemic administration of naked oncolytic Ad.
Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer
Authors: U.A. Matulonis, G.M. Wulf, W.T. Barry, M. Birrer, S.N. Westin, S. Farooq, K.M. Bell-McGuinn, E. Obermayer, C. Whalen, T. Spagnoletti, W. Luo, H. Liu, R.C. Hok, C. Aghajanian, D.B. Solit, G.B. Mills, B.S. Taylor, H. Won, M.F. Berger, S. Palakurthi, J. Liu, L.C. Cantley, E. Winer
Journal: Annals of Oncology (2016)
A Library of Sickle Cell Anemia Induced Pluripotent Stem Cells of Diverse Haplotypes and Ethnicities
Authors: Seonmi Park, Andreia Gianotti-Sommer, David H.K. Chui, Maria Stella Figueiredo, Abdulrahman Alsultan, Amein Al-Ali, Martin H Steinberg, George J. Murphy, Gustavo Mostoslavsky
Journal: Blood (2015)
Abstract 4547: Preparation of peptide-based Shp2 substrates with phosphatase activity-dependent fluorescence
Authors: Steven Gunawan, Yunting Luo, Yuan Ren, Harshani R. Lawrence, Jerry Wu, Nicholas J. Lawrence
Journal: Cancer Research (2015)

Abstract The Shp2 protein tyrosine phosphatase mediates signal transduction of growth factor receptors and regulates cellular activities critical to tumor growth and metastasis. Shp2-activating mutations are associated with several types of leukemias and solid tumors, making Shp2 an attractive target for anticancer development. While there are reports of Shp2 inhibitors, there is a need for compounds with higher potency and improved selectivity. One approach to the discovery of new Shp2 inhibitors is via high throughput screening (HTS) of small molecule libraries. The small molecule probe 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) is currently a widely used substrate for phosphatases and has been used to assay Shp2 activity. However, DIFMUP binds only the catalytic site of the phosphatase and is unlikely to reveal compounds that are selective for Shp2 in an HTS. There is clearly a need to develop probes that are more sensitive and more specific for a particular phosphatase to identify Shp2 selective inhibitors and to measure Shp2 activity. We have developed a new phosphopeptide-like Shp2 substrate that becomes fluorescent upon enzyme-mediated hydrolysis, based on a phosphopeptide sequence that has high affinity for Shp2. We will report details of the novel Shp2 activity probe and its use as a reagent for HTS and determination of Shp2 inhibitor potency. We will also report on its suitability for HTS and preliminary results from screening and its potential for the discovery of novel Shp2 inhibitors. We will discuss the binding mode of the probe, based on novel co-crystal structures of related peptides with Shp2. Citation Format: Steven Gunawan, Yunting Luo, Yuan Ren, Harshani R. Lawrence, Jerry Wu, Nicholas J. Lawrence. Preparation of peptide-based Shp2 substrates with phosphatase activity-dependent fluorescence. [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 4547. doi:10.1158/1538-7445.AM2015-4547
Drug-induced HPA axis alterations during acute critical illness: a multivariable association study
Authors: Bram Peeters, Fabian Güiza, Eva Boonen, Phlippe meersseman, Lies Langouche, Greet Van den Berghe
Journal: Endocrine Reviews (2016)

SummaryObjective
Critical illness is hallmarked by low plasma ACTH in the face of high plasma cortisol. We hypothesized that frequently used drugs could play a role by affecting the hypothalamic–pituitary–adrenal axis.

Design
Observational association study.

Patients
A total of 156 medical-surgical critically ill patients.

Measurements
Plasma concentrations of ACTH and total/free cortisol were quantified upon ICU admission and throughout the first 3 ICU days. The independent associations between drugs administered 24 h prior to ICU admission and plasma ACTH and cortisol concentrations upon ICU admission were quantified with use of multivariable linear regression analyses.

Results
Upon ICU admission, compared with healthy subjects, patients had low mean±SEM plasma ACTH concentrations (2·7 ± 0·6 pmol/l vs 9·0 ± 1·6 pmol/l, P < 0·0001) in the face of unaltered total plasma cortisol (336·7 ± 30·4 nmol/l vs 300·8 ± 16·6 nmol/l, P = 0·3) and elevated free plasma cortisol concentrations (41·4 ± 5·5 nmol/l vs 5·5 ± 0·8 nmol/l, P = 0·04). Plasma ACTH concentrations remained low (P < 0·001) until day 3, whereas plasma (free) cortisol concentrations steeply increased and remained high (P < 0·001). No independent correlations with plasma ACTH were found. In contrast, the total admission plasma cortisol concentration was independently and negatively associated with the cumulative opioid (P = 0·001) and propofol (P = 0·02) dose, the use of etomidate (P = 0·03), and positively with the cumulative dobutamine dose (P = 0·0007).

Conclusions
Besides the known suppressive effect of etomidate, opioids and propofol may also suppress and dobutamine increases plasma cortisol in a dose-dependent manner. The observed independent associations suggest drug effects not mediated centrally via ACTH, but rather peripherally by a direct or indirect action on the adrenal cortex.
Low Incidence of Acute Graft-VS.-Host Disease (GVHD) Using Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) after Matched Sibling Donor (MSD) Non-Myeloablative Stem-Cell Transplants (NST) Conditioned with Fludarabine (FLU) and Low-Dose Total Body Irradiation (TBI).
Authors: Yago Nieto, Nigel Patton, Timothy Hawkins, Ruth Spearing, Scott I. Bearman, Rachel Rabinovitch, Chan Zeng, Anna Baron, Peter A. McSweeney
Journal: Blood (2004)
Abstract 2101: The transcription factor POU3F2 is expressed in human gliomas and promotes tumorigenesis <i>in vivo</i>
Authors: Mohummad Aminur Rahman, Lina Liess, Mohammad S. Lellahi, Christiane H. Gjerde, Halala S. Saed, Ercan Mutlu, Huaiyang Zhu, Jian Wang, Per Øyvind Enger
Journal: Cancer Research (2015)

Abstract The neurodevelopmental transcription factor POU3F2 (also called OCT7 / BRN2) is expressed during neurogenesis. Moreover, POU3F2 expression has been reported as a promoter of proliferation and invasion in malignant melanoma of the skin. Since both melanomas and CNS-malignancies arise in organs of neuro-ectodermal origin, we investigated whether human gliomas expressed POU3F2 and the role of POU3F2 in glioma tumorigenesis. We performed immunohistochemistry of 149 grade II-IV gliomas from our tumor bank, and subsequently performed western blots and qPCR of 12 samples from each grade. In addition, we performed flow cytometric analysis of POU3F2 expression in 5 acutely dissociated tumors. Using lentiviral transfection we established glioma cell lines with POU3F2 overexpression or knock down in order the to investigate the effect of POU3F2 on proliferation, migration and differentiation, both in vitro and in vivo. The mechanism, by which POU3F2 regulates glioma progression, was also investigated. Immunohistochemistry showed that POU3F2 was almost uniformly expressed in human gliomas. Both western blot, qPCR and flow cytometry confirmed expression of POU3F2 in human gliomas. In acutely dissociated tumors, the POU3F2 positive cells displayed an increased cell percentage in the S and G2/M phase of the cell cycle. Moreover, POU3F2 overexpression in the glioma cell lines increased growth rates and colony formation. Overexpression of POU3F2 increased the levels of phosphorylated p-44/42 indicating activation of the ERK1/2 signaling pathway. Increased levels of downstream transcriptional targets c-Myc, Elk1 and Stat3 transcription factors in the POU3F2 overexpressing cell lines confirmed activation of the MAPK signaling pathway. Furthermore, the POU3F2 overexpressing cell lines displayed increased expression of the growth factor FGF2. U0126, an inhibitor of MEK1/2, decreased the cell proliferation and decrease levels of phospho-p44/42, phospho-stat3 and FGF2. Moreover, overexpression of the POU3F2 increases the level of other neurodevelopmental transcription factors associated with a pluripotent state. Ongoing studies aim at further elucidating the multiple roles of POU3F2 in brain tumor progression. Citation Format: Mohummad Aminur Rahman, Lina Liess, Mohammad S. Lellahi, Christiane H. Gjerde, Halala S. Saed, Ercan Mutlu, Huaiyang Zhu, Jian Wang, Per Øyvind Enger. The transcription factor POU3F2 is expressed in human gliomas and promotes tumorigenesis in vivo. [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 2101. doi:10.1158/1538-7445.AM2015-2101
A meta-analysis on impact of age at first pregnancy on the risk of developing breast cancer according to subtype
Authors: A. Levaggi, M. Lambertini, L. Santoro, F.A. Peccatori, L. Del Mastro, D. Ugolini, P. Pronzato, L. Livraghi, H.A. Azim
Journal: Annals of Oncology (2015)
A Randomized, Placebo-Controlled, Phase II Study of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS)
Authors: Guillermo Garcia-Manero, Jesus G. Berdeja, Rami S. Komrokji, James Essell, Roger M. Lyons, Michael Maris, Amy E. DeZern, Mikkael A. Sekeres, Gail J Roboz
Journal: Blood (2015)