tbuckley/cabot-search huggingface dataset:
Abstract 3126: Survival in glioblastoma cancer patients is predicted by miR-340, that regulates key cancer hallmarks by inhibiting NRAS
Authors: Danilo Fiore, Cristina Quintavalle, Elvira Donnarumma, Giuseppina Roscigno, Margherita Iaboni, Valentina Russo, Assunta Adamo, Fabio De Martino, Adelaide Greco, Giulia Romano, Soini Ylermi, Arturo Brunetti, Carlo Maria Croce, Gerolama Condorelli
Journal: Cancer Research (2015)

Abstract Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, patients survival remains poor. Nevertheless, a subset of patients survives longer than 3 years and they are classified as long-term survivors (LTS). The molecular and cellular mechanisms underlying the rare phenomenon of LTS are not well known. MicroRNAs (miRNAs or miRs) are a class of endogenous non-coding RNA of 19-24 nucleotides in length that have an important role in the negative regulation of gene expression. Deregulation of miRNAs is linked to the pathogenesis of many types of cancer. We performed a nanostring miRNA analysis on long and short glioblastoma survivors patients to individuate miRs potentially involved in LTS phenotype. Using this approach, we identified miR-340 as a novel tumor-suppressor-miR in glioblastoma. miR-340 expression was increased in LTS compared to short term survivors. Moreover, a log-rank test analysis on both the data collected from TCGA database and from a cohort of glioblastoma patients present in our lab revealed that low levels of miR-340 were a risk indicator for glioblastoma patients survival. miR-340 overexpression decreased cell proliferation, anchorage independent cell growth, cell cycle and response to temozolomide in different glioblastoma cell lines. We identified NRAS as a direct target of miR-340. Rescue experiments showed its essential role in mediating the onco-suppressive activity of miR-340. The overexpression of miR-340 decreased the activation of ERKs and AKT, the main pathways downstream NRAS. Furthermore, glioblastoma cells stably infected with a lentivirus encoding miR-340 exhibited a drastic reduction of tumor growth in nude mice. In conclusion, our findings reveal miR-340 as a new tumor-suppressor miRNA up-regulated in LTS in glioblastoma. Its expression inversely correlates with survival of glioblastoma patients. miR-340 is able to regulate multiple tumorigenic features of glioblastoma cells, offering a novel potential prognostic and therapeutical target for glioblastoma. Citation Format: Danilo Fiore, Cristina Quintavalle, Elvira Donnarumma, Giuseppina Roscigno, Margherita Iaboni, Valentina Russo, Assunta Adamo, Fabio De Martino, Adelaide Greco, Giulia Romano, Soini Ylermi, Arturo Brunetti, Carlo Maria Croce, Gerolama Condorelli. Survival in glioblastoma cancer patients is predicted by miR-340, that regulates key cancer hallmarks by inhibiting NRAS. [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 3126. doi:10.1158/1538-7445.AM2015-3126
Abstract 1039: Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma cells
Authors: Norihiko Takemoto, Satoshi Serada, Minoru Fujimoto, Hidenori Inohara, Tetsuji Naka
Journal: Cancer Research (2015)

Abstract Background: Leucine-rich α2 glycoprotein (LRG) is an approximately 50 kDa serum glycoprotein. It has been reported that the expression levels of LRG were elevated in the sera and tissues in several cancers. While it has been demonstrated that LRG modulated TGFβ1 signaling in endothelial cells and resulted in the promotion of pathogenic angiogenesis, the precise function of LRG in cancer remains unclear. The aim of this study was to investigate the role of LRG on the cellular response by TGFβ1 in Lewis lung carcinoma (LLC) cells. Methods: Parental LLC, mLRG-overexpressing LLC or control vector transfected LLC cells were subcutaneously transplanted into LRG knockout (KO) or Wild-type (WT) C57BL/6J mice and tumor growth was monitored. Cell proliferation treated with TGFβ1 was evaluated by WST-8 assay. Caspase activity was measured with Caspase-GloTM assay kit, protein expression levels were analyzed by western blotting and gene expression was analyzed with quantitative real-time PCR. LLC tumor growth were monitored in LRG KO or WT mice treated with TGFβRI inhibitor (SB431542) or vehicle. Apoptosis of LLC tumor was evaluated by TUNEL staining. Result: In LRG KO mice, LLC tumor growth was significantly increased compared with that in WT mice. In contrast, overexpression of mLRG significantly inhibited the growth of LLC tumors in WT mice. Treatment of TGFβ1 inhibited the proliferation of LLC cells in vitro. Addition of TGFβ1 strongly inhibited the proliferation of mLRG-overexpressing LLC cells than control vector LLC cells by induction of apoptosis. By TGFβ1 stimulation, induction of apoptosis via activation of smad2 and downstream signaling pathway was significantly increased in mLRG overexpressing LLC compared with control LLC cells in vitro. Treatment of TGFβRI inhibitor significantly enhanced growth and inhibited apoptosis of LLC tumor in WT mice compared with LRG KO mice. Conclusion: We found that LRG promoted TGFβ1-induced apoptosis in LLC, in vitro and in vivo. LRG is involved in the enhancement of TGFβ1-smad signal transduction. Citation Format: Norihiko Takemoto, Satoshi Serada, Minoru Fujimoto, Hidenori Inohara, Tetsuji Naka. Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma 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 1039. doi:10.1158/1538-7445.AM2015-1039
671. Development of a Successful Lyophilization Process for Lentiviral Vector Clinical Batches
Authors: Nicolas Delacroix, Gael Ouengue Mbele, Julien Deroyer, Guillaume Deplaine, Cecile Bauche
Journal: Molecular Therapy (2015)

Since lentiviral vectors are incrinsingly used in various applications (vaccination, gene therapy, T-cell therapies …) and given that so far the best way to keep these vectors is a -80°C storage, more adapted ways of formulation and storage must be developped. Previous attempts have been made to freeze-dry viral vectors: adenovectors and Moloney Monkey Leukemia Virus-based vectors (Cruz et al., 2006) and lentiviral vectors (Shin et al, 2010). None of these attempts have proved satisfactory as the final lyophilized products were not suitable for pharmaceutical applications (mainly due to unacceptable levels of contaminants observed in the final products). We developped an new method to freeze-dry our clinical grade batches of lentiviral vectors. This method allows us to store the batches at -20°C and +4°C while maintaining the characteristics of the particules after reconstitution and the ability to use them as intended (direct injection, T-cell modification …). Our method allows the lyophilization of lentiviral vectors either produced in adherent cells cultures (with FBS) or in suspension cells cultures (without FBS and with synthetic culture medium). The vectors are protected during the freeze-drying process by the addition of a lyoprotectant (sucrose or threalose) and stability is evaluated over time. Quality controls have been performed to evaluate the impurity profiles of the lentivector batches before the freeze-drying process and after the reconstitution of the particules (titer, total proteins, total DNA, HEK 293T proteins), and we demonstrated that the profiles were not impacted by the process and that the batches were still fitting the international pharmacopea recomandations.. We also made some immunogenicity evaluation of our vaccine candidates before and after the lyophilization process, and we were able to show that the process had no impact on the breadth and intensity of the cellular immune response we are able to elicit after a direct injection of the reconstituted particles in mice. THERAVECTYS is a Paris-based, privately-owned, fully integrated discovery & clinical development biotech company. THERAVECTYS develops lentiviral vectors used for human vaccination and immunotherapy applications (CAR-T cells and TCR). An in house cGMP facility is now up and running, allowing us to produce and charaterize our own lentiviral vector clinical batches. A qualified freeze-dryer has been installed in the plant, to systematically encompass this formulation and repartition step in our bioproduction processes.
Identification of An Abnormal JAK2 WT CD34+ Cell Population Characterized by High Bcl-Xl Expression Levels Both in JAK2 Positive and Negative PV, ET and PMF Patients,
Authors: Daniela Cilloni, Valentina Rosso, Marina Podestà, Enrico Bracco, Federica Benvenuto, Sonia Carturan, Giovanni Barosi, Vittorio Rosti, Giuseppe Saglio, Francesco Frassoni
Journal: Blood (2011)
Abstract 1763: Activation of p53/miR-34a tumor suppressor network by Chinese herbal recipe JP-1 in human lung cancer cells
Authors: Chih-Jung Yao, Peter Sheng, Tsai-Shu Hu, Jacqueline Wang-Peng, Gi-Ming Lai
Journal: Cancer Research (2015)

Abstract Non-small cell lung cancer (NSCLC) is one of the most common cancers worldwide. In spite of the recent progress in targeted therapy, most of the patients eventually expired due to the inevitable recurrence and drug resistance. New integrated therapeutics with evidence based molecular mechanism is urgently needed. MiR-34a, a direct target of p53, is a well-characterized tumor suppressor miRNA in a variety of cancers. How to restore the p53/miR-34a regulatory axis has becomes an important novel strategy for cancer therapy. Here, we show that a Chinese herbal recipe JP-1 activates p53/miR-34a tumor suppressor network in human NSCLC A549 cells (p53 wild type). Treatment of A549 cells with JP-1 extract (38% ethanol) induced profound apoptosis accompanied with marked elevation of p53 and its downstream p21 and Bax protein levels. Accordingly, increase of miR-34a was also observed. Analyzing the miR-34a downstream targets in JP-1-treated cells, we found the decrease of survival factors such as Sirt1 and survivn. Nevertheless, JP-1 also decreased Axl, an important invasion-related miR-34a downstream, while increased E-cadherin expression. The JP-1-activated p53/miR-34a tumor suppressor network coincided with mitochondrial-dependent apoptosis induction and EMT (epithelial-mesenchymal transition) inhibition. In agreement with this, JP-1 induced phospho-AMPKα but inhibited phospho-AKT protein level. Our results might interpret the clinical benefit observed in JP-1-treated patients and suggest its potential as a complementary medicine for NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Chih-Jung Yao, Peter Sheng, Tsai-Shu Hu, Jacqueline Wang-Peng, Gi-Ming Lai. Activation of p53/miR-34a tumor suppressor network by Chinese herbal recipe JP-1 in human lung 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 1763. doi:10.1158/1538-7445.AM2015-1763
Abstract LB-097: Targeted degradation of the androgen receptor in prostate cancer
Authors: Meizhong Jin, James D. Winkler, Kevin Coleman, Andrew P. Crew, AnnMarie K. Rossi, Ryan R. Willard, Hanqing Dong, Kam Siu, Jing Wang, Deborah A. Gordon, Xin Chen, Caterina Ferraro, Craig M. Crews, Taavi K. Neklesa
Journal: Cancer Research (2015)

Abstract Progression of prostate cancer in patients treated with anti-androgen therapy usually involves several mechanisms of enhanced Androgen Receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression and AR mutations. We have developed a protein degradation technology called PROTACs (PROteolysis TArgeting Chimera), which uses bi-functional molecules that simultaneously bind a target of choice and an E3 ligase. PROTACs, via induced proximity, cause ubiquitination and degradation of the targeted, pathological protein. As opposed to traditional target inhibition, which is a competitive process, degradation is a progressive process. As such, it is less susceptible to increases in endogenous ligand, target expression, or mutations in the target. Thus this technology seems ideal for addressing the mechanisms of AR resistance in patients with prostate cancer. AR PROTACs were shown to degrade AR in LNCaP and VCaP cells, with low nM to pM potency, and had a &amp;gt;85% reduction in AR concentration (Dmax). Degradation was rapid, with 50% of AR lost within 15 minutes and maximal degradation observed by 4 hours. The degradation process in cells was specific, as the PROTAC activity can be competed with excess E3 ligand and PROTACs with an inactive epimer for E3 ligase binding did not degrade AR. AR PROTACs induced rapid apoptosis and cell death in VCaP cells. In LNCap and VCaP cell systems, AR PROTACs were anti-proliferative under conditions in which enzalutamide was inactive, such as increasing concentrations of the AR agonist R1881 and cells containing the ARF876L mutation. AR PROTACs typically exhibited good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of &amp;gt;50% after ip or sc injection. In mice, AR PROTACs demonstrate in vivo activity, including reduction of AR protein levels, prostate involution and tumor growth inhibition. In summary, PROTACs designed to degrade AR are potent, specific, active in vitro and in vivo, and have cellular efficacy superior to enzalutamide. Targeted degradation of AR may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed. Citation Format: Meizhong Jin, James D. Winkler, Kevin Coleman, Andrew P. Crew, AnnMarie K. Rossi, Ryan R. Willard, Hanqing Dong, Kam Siu, Jing Wang, Deborah A. Gordon, Xin Chen, Caterina Ferraro, Craig M. Crews, Taavi K. Neklesa. Targeted degradation of the androgen receptor in prostate 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-097. doi:10.1158/1538-7445.AM2015-LB-097
Efficacy and safety of gefitinib and potential prognostic value of soluble EGFR, EGFR mutations, and tumor markers in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer
Authors: K. K. Leslie, M. W. Sill, K. M. Darcy, A. T. Baron, J. A. Wilken, A. K. Godwin, L. Cook, R. J. Schilder, J. M. Schilder, N. J. Maihle
Journal: Journal of Clinical Oncology (2009)

e16542 Background: A phase II trial was performed to evaluate the efficacy and safety of gefitinib and to explore epidermal growth factor receptor (EGFR, sEGFR), estrogen receptor (ER) and progesterone receptor (PRA, PRB) expression in persistent/recurrent endometrial cancer (EC). Methods: Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 500 mg oral gefitinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with PFS at 6 months as the primary endpoint. The trial had a 10% type I error rate with 90% power. sEGFR was quantified in serum and categorized at the median (1960 fmol/ml). Mutations in exons 18–21 of EGFR and IHC-expression of EGFR, pEGFR, ER, PRA, PRB, pERK, or Ki67 were examined in tumors. Results: Of the 29 enrolled, 26 were evaluable for efficacy and toxicity. Four had PFS ≥6 months, 1 had a complete response, 7 had stable disease, 16 had progressive disease and 2 were indeterminate. High pre-cycle 1 sEGFR level was favorably associated with OS (hazard ratio = 0.33, 95% confidence interval = 0.13–0.84). A mutation in exon 18 of EGFR (E709K) was observed but was not associated with clinical outcome. None of the tumor markers was associated with response, PFS, or OS. Among some of the notable correlations observed in primary tumor expression were ER with PRA (r = 0.504), EGFR with pERK (r = 0.802), and pEGFR with pERK (r = 0.728). Changes in expression were notable for pEGFR (increasing) and pERK (increasing) in primary versus pre-treatment persistent/recurrent tumor. Conclusions: The regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting, however, the association between serum sEGFR and OS, correlations between tumor markers, and changes in expression of pEGFR and pERK are interesting and should be validated in future investigations. This study was supported by NIH grant R01CA099908 and NCI grants CA27469, CA11479 and CA37517. No significant financial relationships to disclose.
10-Days Concomitant Therapy, 10-Day Bismuth Quadruple Therapy, and 14-Day Triple Therapy in the First Line Treatment of Helicobacter Pylori Infection - A Multicenter Randomized Trial
Authors: Po-Yueh Chen, Jyh-Ming Liou, Yu-Jen Fang, Chieh-Chang Chen, Chi-Yang Chang, Jeng-Yih Wu, Ming-Jong Bair, Jaw-Town Lin, Ming-Shiang Wu
Journal: Clinical Gastroenterology and Hepatology (2016)
IMCT-11NEXT GENERATION T CELL RECEPTOR SEQUENCING CAN IDENTIFY, QUANTIFY, AND TRACK TUMOR-SPECIFIC T CELL POPULATIONS BEFORE AND AFTER DENDRITIC CELL VACCINATION IN GLIOBLASTOMA MULTIFORME PATIENTS
Authors: Shaina Sedighim, Melody Hsu, Joseph Antonios, Ryan Emerson, Erik Yusko, Catherine Sanders, Tom Davidson, Linda Liau, Robert Prins
Journal: Neuro-Oncology (2015)

While dendritic cell vaccination is a promising treatment for glioblastoma (GBM), sensitive methods of monitoring the immune response after treatment remain to be established. We sought to determine whether: 1) T cell receptor (TCR) repertoire overlap between peripheral blood and tumor and 2) tumor infiltrating lymphocyte (TIL) content, as assessed by next generation DNA sequencing, are predictors of immune response and survival. Genomic DNA from pre and post treatment tumor, as well as pre and post treatment peripheral blood, of 16 GBM patients enrolled in Phase I and II DC vaccination clinical trials was subjected to next generation sequencing through the TCRVβ region to quantify TIL content and assess the overlap between tumor and blood. Of the 5 patients for whom initial and relapsed tumors were available, two patients with high TCR sequence overlap between tumor and blood prior to treatment demonstrated the longest overall survival (OS) of 71.3 and 28.7 months. Two patients with poor OS (6.3 and 4.5 months) had low blood and tumor TCR overlap both before and after treatment. One multi-focal recurrent patient with intermediate OS (12.6 months) demonstrated an initially low overlap between pre-treatment tumor and blood; however, the TCR overlap increased 200-fold after treatment. Because we did not possess post-treatment, relapsed tumors for many patients, we tested whether the density of pre-treatment TILs was relevant. For the 16 patients from whom we had pre-treatment tumor tissue, the estimated TIL content significantly correlated with time to progression and OS (HR = 0.252, p = 0.0442; HR = 0.277, p = 0.0461), respectively. The estimated TIL content of pre-treatment tumor directly correlates with survival in GBM patients who received autologous tumor lysate-pulsed DC vaccination. Furthermore, the trends of tumor and peripheral blood TCR overlap suggest that this technology can be utilized to track tumor-specific T cell populations without prior knowledge of their antigen specificity.
Inhibition of the Notch1 Pathway in Chronic Lymphocytic Leukemia Promotes Apoptosis and Inhibits Proliferation
Authors: Josephine L. Klitgaard, Reuma Magori-Cohen, Reina Improgo, Stacey M. Fernandes, Bethany Tesar, Kevin Hoang, Haesook T Kim, Jennifer R. Brown
Journal: Blood (2014)
DRES-11. A CROSS-ACTIVATING c-Met/β1 INTEGRIN COMPLEX DRIVES THERAPEUTIC RESISTANCE IN GLIOBLASTOMA
Authors: Arman Jahangiri, Maxim Sidorov, Sung Won Han, William Chen, Jonathan Rick, Dina Schneidman-Duhovny, Smita Mascharak, Michael De Lay, Jeffrey Wagner, Brandyn Castro, Brandon Imber, Patrick Flanigan, Ruby Kuang, Kan Lu, Gabriele Bergers, Andrej Sali, William Weiss, Manish Aghi
Journal: Neuro-Oncology (2016)

Invasive resistance limits anti-angiogenic cancer therapies. While c-Met and β1-integrin are implicated, the mechanism by which they drive resistance remains unclear. We investigated the hypothesis that chemotactic c-Met and haptotactic β1-integrin structurally and functionally interact, driving invasive resistance in glioblastoma. Immunoblotting, immunohistochemistry, and immunoprecipitation of resistant xenografts and patient specimens along with Pymol modeling of crystal structures were used to assess c-Met/β1-integrin interaction. We identified a c-Met/bβ1-integrin complex in bevacizumab-resistant tumors. Hypoxia upregulated complex formation, while VEGF165 binding VEGFR2 sequestered c-Met and β1-integrin, preventing complex formation. Far-western blots showed only c-Met’s extracellular domain to bind β1-integrin. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and the c-Met/β1 complex maintaining the high-affinity β1-integrin conformation. Complex induction via iDimerize, harboring complementary proteins tagged to β1-integrin and c-Met, increased migration and survival under hypoxia and nutrient deprivation that defines anti-angiogenic therapy resistance (P<0.05). c-Met bound α5 integrin-binding site of β1-integrin, with c-Met/β1 binding fibronectin better than α5β1. Site-directed biopsies from a bevacizumab-resistant glioblastoma patient revealed increased complex formation progressing from core to enhancing-edge to invasive cells outside enhancement. PLAs revealed 20-fold more c-Met/β1 complexes after bevacizumab resistance in patient specimens versus a two-fold increase in recurrent bevacizumab-naïve glioblastomas (P<0.05). The percentage of β1-integrin bound to c-Met in 20 patient glioblastomas at diagnosis correlated inversely with survival (P<0.05). We demonstrated that therapy-induced changes in the tumor microenvironment enable tumor cells to co-opt normal receptors promoting two modes of cell migration: chemotaxis, movement towards concentrations of chemoattractants, and haptotaxis, movement controlled by relative strengths of peripheral adhesions. These receptors are then redirected away from their normal binding partners, forming a structural complex driving ligand-independent cross-activation and enhanced binding of the extracellular matrix. The c-Met/β1 complex thus drives and is a powerful mechanistic biomarker for invasive anti-angiogenic therapy resistance.
ENU Mutagenesis in the Mouse for Identification of Genes Regulating Erythropoiesis: a Mouse Mutant with An Activating Mutation of the KCl Cotransporter, KCC1 Causing Dehydrated Red Cells
Authors: David J. Curtis, Fiona Brown, James Wiley, Shwen Ho, Douglas J. Hilton, Benjamin T. Kile, Stephen M Jane
Journal: Blood (2011)