tbuckley/cabot-search huggingface dataset:
Abstract 2505: GNA13 induction of stemness and resistance to chemotherapy in breast and head and neck cancers
Authors: Hui Sun Leong, Suhail Ahmed Kabber Rasheed, Manikandan Lakshmanan, Anandh Kumar Raju, Vinay Tergaonkar, Daniel shao-Weng Tan, Patrick Casey, N.Gopalakrishna Iyer
Journal: Cancer Research (2016)

Abstract Despite advancement in cancer therapy, the ability of cancer cells to evade therapy often leads to tumor recurrence and distant metastasis, and ultimately to the death of the patient. Increasing evidence shows that these properties of recurrence can be attributed to a small population of cells within the tumor termed cancer stem cells (CSCs). Understanding the mechanisms that support the growth of CSCs could provide new tools to target these cells and improve therapeutic outcomes. G12 proteins, comprised of Gα12 (GNA12) and Gα13 (GNA13) are mediators of G protein coupled receptor (GPCR) signaling. These proteins are highly expressed in several cancers, and blocking their signaling can significantly inhibit cancer cell invasion and metastasis. Recently, we have shown that loss of GNA13 alone can suppress invasion of breast and prostate cancer cells. Moreover, we have recently obtained evidence that enhanced expression of GNA13 is capable of inducing a stem cell phenotype in cancer cells. Specifically, enforced expression of GNA13 in cancer cells containing low levels of GNA13 protein significantly induced CSC population as shown by increased aldehyde dehydrogenase (ALDH1) activity, increased CD44+/CD24− cells, and enhancement of tumor sphere formation. In contrast, in cancer cells that express high levels of GNA13, knockdown of GNA13 suppressed ALDH1 activity, the CD44+/CD24− cell population, and the formation of spheres. Using reporter assays we have identified that GNA13 induced CSC phenotype most probably via activating Jun Kinase - AP1 signaling pathway and blocking this pathway could significantly inhibit CSC phenotype induced by GNA13. Most importantly we have identified that GNA13 expressing cells are resistant to most commonly used chemotherapeutic agents and ionizing radiations. Blocking GNA13 using shRNAs sensitized these cells to both chemo- and radiotherapy significantly. We therefore hypothesize that GNA13 plays a pivotal role in the induction of CSCs and drug resistance, and the suppression of GNA13 activity may provide therapeutic advantage to cancer therapy. Citation Format: Hui Sun Leong, Suhail Ahmed Kabber Rasheed, Manikandan Lakshmanan, Anandh Kumar Raju, Vinay Tergaonkar, Daniel shao-Weng Tan, Patrick Casey, N.Gopalakrishna Iyer. GNA13 induction of stemness and resistance to chemotherapy in breast and head and neck cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2505.
Abstract 2769: Response to 5FU therapy in colorectal cancer is affected by EZH2-mediated BclX splicing
Authors: Natalya Benderska, Maria Gazouli, Gerasimos Aravantinos, Arndt Hartmann, Regine Schneider-Stock
Journal: Cancer Research (2016)

Abstract Background and Aims: The chromatin modifier EZH2 is remarkably up-regulated in many cancer types including colon cancer. High levels of EZH2 have been correlated with tumor metastasis and regulation of tumor-initiating cell subpopulation. Since, DZNep, an EZH2 inhibitor, can inhibit the growth capability of colon cancer by inducing apoptosis; down-regulation of EZH2 seems to be a promising therapeutic approach. Our preliminary data showed that EZH2 levels were remarkably increased in blood samples from metastatic colorectal cancer patients who did not respond to the combination therapy with bevacizumab-irinotecan-5FU in comparison to patients who were responders and developed a stable disease. Many apoptosis-related proteins possess a dual function (pro- and anti-apoptotic) due to alternative splicing. Therefore we aimed to find possible apoptosis-associated EZH2 targets to explain these interesting findings. Methods: HCT116 colon cancer cells were used for DZNep and 5FU treatment and its efficiency was verified by Western blot analysis. In vivo splicing assay was performed using BclX minigene construct. The mRNA expression of EZH2, caspase 2, Death-associated protein kinase (DAPK) and BclX isoforms was assessed by quantitative real-time PCR in cells (BclX also in blood of patients) and normalized to the GAPDH. Cell viability was examined by Crystal Violet staining. Results: Western Blot for caspase 3 cleavage indicated increased apoptotic levels after DZNep treatment. Combined DZNep and 5FU treatment of cells led to a synergistic effect in reducing cell viability. DZNep treatment specifically promoted pro-apoptotic BclXs isoform, but did not affect the shift of pro-apoptotic isoforms of caspase 2 and DAPK. Using a BclX minigene transfection we confirmed this effect exogenously. The ratio BclXs/Xl was significantly altered by overexpression of different splicing factors such as ASF/SF2, Sam68, after DZnep treatment. Moreover, patients who did not respond to the combination therapy had the highest EZH2 and BclXl isoform levels. Conclusion: Our data indicate a new interesting link between epigenetic regulation and the splicing machinery. Detailed investigation of EZH2-mediated regulation of BclXs/Xl ratio could have the potential for prediction of 5FU-based therapy response in colon cancer patients. Citation Format: Natalya Benderska, Maria Gazouli, Gerasimos Aravantinos, Arndt Hartmann, Regine Schneider-Stock. Response to 5FU therapy in colorectal cancer is affected by EZH2-mediated BclX splicing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2769.
Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia
Authors: Asuka Honjo, Nobuhiro Nakano, Susumu Yamazaki, Mutsuko Hara, Koichiro Uchida, Jiro Kitaura, Chiharu Nishiyama, Hideo Yagita, Yoshikazu Ohtsuka, Hideoki Ogawa, Ko Okumura, Toshiaki Shimizu
Journal: Journal of Allergy and Clinical Immunology (2016)
Hypocholesterolemia Is Independently Associated with Decreased Survival in Patients with Primary Myelofibrosis: An Analysis of Lipid Profiles in 558 Myeloproliferative Patients.
Authors: Ruben A. Mesa, Jocelin Huang, Susan Schwager, Animesh Pardanani, Kebede Hussein, David Dingli, Michael Jensen, Elizabeth Haglind, Ayalew Tefferi
Journal: Blood (2007)
Preventive CNS Irradiation with 12 Gy Compared to 18 Gy: Results of Studies AML-BFM 98 and 2004.
Authors: Ursula Creutzig, Martin Zimmermann, Joerg Ritter, Norbert Graf, Thomas Lehrnbecher, Jean-Pierre Bourquin, Arend Stackelberg, Michael N Dworzak, Jan Starý, Dirk Reinhardt
Journal: Blood (2009)
Sequencing of the genus Arabidopsis identifies a complex history of nonbifurcating speciation and abundant trans-specific polymorphism
Authors: Polina Yu Novikova, Nora Hohmann, Viktoria Nizhynska, Takashi Tsuchimatsu, Jamshaid Ali, Graham Muir, Alessia Guggisberg, Tim Paape, Karl Schmid, Olga M Fedorenko, Svante Holm, Torbjörn Säll, Christian Schlötterer, Karol Marhold, Alex Widmer, Jun Sese, Kentaro K Shimizu, Detlef Weigel, Ute Krämer, Marcus A Koch, Magnus Nordborg
Journal: Nature Genetics (2016)

Magnus Nordborg and colleagues report a genomic analysis of all 27 known species in the genus Arabidopsis. They find evidence for a complex speciation history that is not accurately reflected by a traditional bifurcating species tree and identify widespread shared polymorphisms between species. The notion of species as reproductively isolated units related through a bifurcating tree implies that gene trees should generally agree with the species tree and that sister taxa should not share polymorphisms unless they diverged recently and should be equally closely related to outgroups. It is now possible to evaluate this model systematically. We sequenced multiple individuals from 27 described taxa representing the entire Arabidopsis genus. Cluster analysis identified seven groups, corresponding to described species that capture the structure of the genus. However, at the level of gene trees, only the separation of Arabidopsis thaliana from the remaining species was universally supported, and, overall, the amount of shared polymorphism demonstrated that reproductive isolation was considerably more recent than the estimated divergence times. We uncovered multiple cases of past gene flow that contradict a bifurcating species tree. Finally, we showed that the pattern of divergence differs between gene ontologies, suggesting a role for selection.
Microenvironmental Interactions up-Regulate CD20 Expression in CLL B Cells through the CXCR4/SDF-1 Axis: Implications for CD20-Targeting Antibodies and the Use of BCR-Inhibitors in Combination
Authors: Gabriela Pavlasova, Vaclav Seda, Marek Borsky, Katerina Cerna, Jitka Osickova, Jiri Mayer, Sarka Pospisilova, Matthew S. Davids, Jennifer R. Brown, Marek Mraz
Journal: Blood (2015)
Abstract 1228: Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis
Authors: Arumugam Nagalingam, Dimiter. B Avtanski, Joesph Tomaszewski, Risbood Prabhakar, Michael Difillippantonio, Brian Mears, Neeraj Saxena, Sanjay Malhotra, Sanjay Malhotra, Dipali Sharma
Journal: Cancer Research (2016)

Abstract The tumor suppressor p53 plays a critical role in suppressing cancer growth and progression and is the most frequently mutated and functionally inactivated gene in all human malignancies. Owing to its widespread alteration/inactivation in cancer, p53 is an attractive target for the development of new targeted therapies. We synthesized several indolo-pyrido-isoquinolin based alkaloids to restore/activate p53 function and examined their therapeutic efficacy using NCI-60 screening. Here, we provide molecular evidence that one of these compounds, 11-Methoxy-2,3,4,13-tetrahydro-1H-indolo[2’,3’:3,4]pyrido[1,2-b]isoquinolin-6-ylium-bromide (termed P18 or NSC-768219) inhibits growth and clonogenic potential of cancer cells. P18 treatment results in downregulation of mesenchymal markers and concurrent upregulation of epithelial markers as well as inhibition of migration and invasion. Experimental epithelial-mesenchymal-transition (EMT) induced by exposure to TGFβ/TNFα is also completely reversed by P18. Importantly, P18 also inhibits mammosphere-formation along with a reduction in the expression of stemness factors, Oct4, Nanog and Sox2. We show that P18 induces expression, phosphorylation and accumulation of p53 in cancer cells. P18-mediated induction of p53 leads to increased nuclear localization and elevated expression of p53 target genes. Using isogenic cancer cells differing only in p53 status, we show that the alteration of mesenchymal and epithelial genes, inhibition of migration and invasion of cancer cells mediated by P18 is p53-dependent. Furthermore, P18 increases miR-34a expression in p53-dependent manner and inhibition of mammosphere-formation by P18 is further enhanced by miR-34a mimic. Collectively, these data provide evidence that p53-miR-34a activation by P18 may represent a promising therapeutic strategy for the inhibition of growth and progression of cancer. Citation Format: Arumugam Nagalingam, Dimiter. B Avtanski, Joesph Tomaszewski, Risbood Prabhakar, Michael Difillippantonio, Brian Mears, Neeraj Saxena, Sanjay Malhotra, Sanjay Malhotra, Dipali Sharma. Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1228.
Preliminary results of PI3Kδ inhibitor idelalisib (GS-1101) treatment in combination with everolimus, bortezomib, or bendamustine/rituximab in patients with previously treated mantle cell lymphoma (MCL).
Authors: Nina D. Wagner-Johnston, Sven De Vos, John Leonard, Jeff Porter Sharman, Marshall T. Schreeder, Ralph V. Boccia, Jacqueline Claudia Barrientos, Steven E. Coutre, Ian Flinn, Thomas E. Boyd, Leanne Holes, David Michael Johnson, Yeonhee Kim, Roger D. Dansey, Wayne R. Godfrey, Nathan Hale Fowler
Journal: Journal of Clinical Oncology (2013)

8501 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown monotherapy activity in recurrent MCL (Kahl, ICML 2011). Methods: This phase 1 study is evaluating the activity of continuous idelalisib (Id), 150 mg BID, in combination with everolimus (E) (10 mg PO qD) (Id+E regimen), with bortezomib (V) (1.3 mg/m 2 SC day 1, 8, 15 per 28 day cycle) (Id+V regimen), or with rituximab (R) (375 mg/m 2 , on Day 1) and bendamustine (B) (90 mg/m 2 x 2), for 6 cycles (Id+BR regimen). Investigators assessed response according to standard criteria (Cheson 2007). Results: Study enrolled 22 patients with relapsed/refractory MCL. Results are from 14 Jan 2013 data cutoff. The 3 cohorts included Id+E (N=12), Id+V (N=6), and Id+BR (N=4). Patients were 73% male, median age [range] of 68 [47E79] years, 32% with refractory disease and 73% stage III/IV. The median [range] number of prior therapies was 3 [1E7]. The median [range] duration of treatment was 2.5 [0.5-8.3+] months. Overall response rate (ORR) was 10/22 (46%), with 2 CR (9%). The ORR/CR for Id+E, was 25%/0%, Id+V was 50%/0%, and Id+BR was 100%/50%. The median duration of response (mDOR) and median PFS (mPFS) were not reached. Most common adverse events included (total%/≥G3%) diarrhea (41/9), fatigue (41/0), rash (27/14), cough (27/0), decreased appetite (23/0), and epistaxis (23/0). Lab abnormalities included (total%/≥G3%) thrombocytopenia (82/27), neutropenia (32/14), and ALT/AST elevations (50/5). Conclusions: Preliminary data indicates idelalisib-based combination therapy is active in patients with relapsed/refractory MCL. All combinations were tolerable. These data support further clinical development in larger trials to further characterize safety and response duration. Clinical trial information: NCT01088048.
Abstract 2705: A computational algorithm to predict tumor growth and cancer stem cell proportion in-vitro and in-vivo from single-cell observations
Authors: Alexander T. Pearson, Patrick Ingram, Shoumei Bai, Euisik Yoon, Trachette Jackson, Ronald J. Buckanovich
Journal: Cancer Research (2016)

Abstract We have developed a new mathematical algorithm and corresponding computer software that uses observations of single cell behavior to predict the growth of the cancer stem-like cell proportion in larger cancer cell groups. Cancer stem-like cells (CSCs) have been implicated in ovarian cancer tumor growth, chemotherapy resistance, and disease recurrence. Aldehyde dehydrogenase (ALDH) is a primary discriminator of CSCs in ovarian cancer as well as in other cancer types. Unfortunately, the rarity and ability of CSCs to rapidly differentiate makes them difficult to study in-vitro and in-vivo. Microfluidic capture devices now allow us to grow and evaluate single ovarian cancer cells in isolated culture. We deployed microfluidic devices to evaluate the different self-renewal and asymmetric division patterns of ALDH+ and ALDH(-) ovarian CSCs. We analyzed data gathered from arrays of single cell chamber observations and found that purified ALDH+ cells were more proliferative than ALDH(-) cells in both cell-line (n = 112, p &amp;lt; 0.001) and primary (n = 41, p = 0.008) ovarian cancer specimens. Importantly, ALDH+ cells could produce both ALDH+ and ALDH(-) cells, whereas ALDH- cells were only able to produce ALDH- cells. Based on this hierarchy-defining data, we developed an easy to use computer algorithm on the freely-available software R to predict cancer cell population growth in-vitro and in-vivo. In our algorithm, size changes of cell populations are simulated by drawing from observed events. We compared the predictions from our hybrid microfluidics chip and computational algorithm with validation experiments in-vivo and in-vitro for both cell line and primary ovarian cancer cells. We found a superb correlation between observed and predicted in-vitro total and CSC counts for both cell line and primary ovarian cancer cells (correlation r = 0.98, p &amp;lt; 0.0001). Furthermore, this approach appropriately predicted changes in cell growth in the presence of the CSC-promoting growth factor EGFL6 both in vitro and in vivo, over time frames of up to 28 days. The single cell division based sampling algorithm developed here allows for rapid and inexpensive means to predict in-vivo ovarian tumor growth based on microfluidic chip culture and can easily be adapted to evaluate new therapeutic options across other cancer subtypes. Citation Format: Alexander T. Pearson, Patrick Ingram, Shoumei Bai, Euisik Yoon, Trachette Jackson, Ronald J. Buckanovich. A computational algorithm to predict tumor growth and cancer stem cell proportion in-vitro and in-vivo from single-cell observations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2705.
Phase II study of danusertib (D) in advanced/metastatic colorectal and pancreatic cancers (CRC, PC).
Authors: B. Laffranchi, M. J. De Jonge, E. Bajetta, A. Hendlisz, R. Giuliani, C. Barone, E. Endlicher, M. G. Jannuzzo, R. Spinelli, A. Santoro
Journal: Journal of Clinical Oncology (2010)

e13558 Background: D is a pan-aurora kinases inhibitor also active against other kinases with oncogenic potential, such as TRKA, RET, FGFRs, ABL. D has been showed to be active against a wide range of cancer cell lines in vitro, in xenografts, spontaneous and transgenic animal tumor models. Methods: Eligible PC patients were relapsing after 1 prior chemotherapy (CT) line for advanced/metastatic disease, CRC patients after 2 prior CT lines. We performed a phase II clinical trial according to a Simon two-stage design. The progression-free rate at 4 months (PFR-4) was the primary endpoint and the number of successes to be observed for proceeding to the second stage were to be ≥ 6/22 evaluable pts for CRC and ≥ 8/28 for PC. D was administered every 14 days, over 24-hour IV infusions of 500 mg/m2. Results: In CRC 33 pts (23 males [M]), median age 62 [38-77] years, were treated. Six pts were not evaluable for efficacy due to early PD (5) or consent withdrawal (1). No pt was progression free at 4 months. In PC 35 pts (15 M), median age 58 [39–80] years, were treated but 4 were not evaluable for efficacy: 3 due to early PD and 1 for consent withdrawal. Three pts were free from progression at 4 months and the second step could not be opened. Grade (G) 3/4 neutropenia was reported in 81% of the 68 treated pts. G3/4 lymphocytopenia, anemia and thrombocytopenia concerned 10, 3 and 1 pts, respectively. The most common drug related G 3/4 events were fatigue (7 pts), febrile neutropenia (6 pts) and diarrhea (5 pts). Neutropenic sepsis occurred in 4 pts. D plasma concentrations at the end of the infusions and pre-dose in different cycles were in line with those obtained in phase I studies. Conclusions: At this dose and schedule D single agent showed acceptable toxicity. D was not active in third-line treatment for metastatic CRC. It has limited activity in second-line treatment of PC pts in terms of disease stabilization: 3 pts out of 31 evaluable remained stable for 6 to 8.5 months. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Accelera, Nerviano Medical Sciences
Abstract 1605: Cetuximab inhibits migration, invasion, metastasis and epithelial-mesenchymal transition but not proliferation via GEP100-Arf6-AMAP1 pathway in head and neck squamous cell carcinoma
Authors: Yoshifumi Matsumoto, Hiroyuki Sakurai, Yasunao Kogashiwa, Koichiro Saito
Journal: Cancer Research (2016)

Abstract Background: Recently, irradiation combined with Cetuximab (Cmab) is being one of the standard therapeutic options against head and neck squamous cell carcinoma (HNSCC), especially in advanced/recurrent cases. While this concurrent chemo-radiotherapy is widely accepted and tolerated, Cmab monotherapy has been reported to be unsatisfactory to treat HNSCC, and detailed mechanism of Cmab to show such clinical efficacy is unknown. Methods: To assess the impact of Cmab on proliferation, migration, and invasion of HNSCC, WST assay, wound healing assay, and matrigel invasion assay were incorporated in this study. Effects of Cmab on the grade of epithelial-mesenchymal transition (EMT), expression level of membrane type 1-matrix-metalloproteinase (MT1-MMP), and activity of EGFR-GEP100-Arf6-AMAP1 pathway, were evaluated using the immunocytochemistry, western blot analysis and Arf6 activation assay, respectively. Furthermore, In vivo efficacy of Cmab was evaluated in highly aggressive and metastatic HSC-3-M3 cells using orthotopic xenograft model in nude mice nu/nu. Results: Inhibition of migration and invasion were observed in 4 HNSCC cell lines by Cmab application. However, proliferation potential of HNSCC were not affected by this chemotherapeutic agent. Increased expression of E-cadherin, with decreased expression of N-cadherin and MT1-MMP, were observed after Cmab treatment in vitro to suggest that Cmab may inhibit EMT in HNSCC. Furthermore, inhibition of Tyr 1086 phosphorylation in EGFR, as well as the inactivation of Arf6 coupled with suppression of both GEP100 and AMAP1 expressions were observed by Cmab application. These results suggested that Cmab might have the potential to suppress the activity of EGFR-GEP100-Arf6-AMAP1 pathway. Furthermore, less metastasis of the cancer was observed in the Cmab treatment group compared with control group in vivo. Conclusions: Our study is the first to provide that Cmab could affect HNSCC through inhibition of migration and invasion of cancer cells, regardless of its anti-proliferative action. EMT inhibition after Cmab application was also clarified in this study. Furthermore, our study suggested that EGFR-GEP100-Arf6-AMAP1 pathway may have some role in the invasion and metastasis of HNSCC. Future studies to further assess the precise mechanism of Cmab against HNSCC are warranted. Citation Format: Yoshifumi Matsumoto, Hiroyuki Sakurai, Yasunao Kogashiwa, Koichiro Saito. Cetuximab inhibits migration, invasion, metastasis and epithelial-mesenchymal transition but not proliferation via GEP100-Arf6-AMAP1 pathway in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1605.