tbuckley/cabot-search huggingface dataset:
P08.06 Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients
Authors: T. Urup, L. Staunstrup, S. Michaelsen, K. Vitting-Seerup, M. Bennedbæk, A. Toft, H. Broholm, P. Hamerlik, H. Poulsen, U. Lassen
Journal: Neuro-Oncology (2016)

AbstractBackground:Bevacizumab combined with chemotherapy is among the most frequently used treatments in recurrent glioblastoma, and patients who achieve response to bevacizumab have improved survival as well as quality of life. The aim of this study was to investigate transcriptional changes associated with response and resistance to bevacizumab therapy.Material and Methods:The study included 21 recurrent glioblastoma patients who were response evaluable and had biomarker assessable tumor tissue surgically removed both before bevacizumab treatment and at time of progression. Patients were grouped into responders (n = 7) and non-responders (n = 14). Gene expression profiling of formalin-fixed paraffin-embedded tumor tissue was performed using RNA-sequencing. Differentially expressed genes were identified by comparing pretreatment samples of responders with those of non-responders and by pairwise comparison of pre- and posttreatment samples in responders and non-responders, separately. False discovery rate adjusted p-values < 0.05 were considered significant. Significant genes were analyzed by functional data mining.Results:There was no significant difference when comparing the transcriptional profile of responders with non-responders prior to initiation of bevacizumab therapy. In non-responders, we identified 1 differentially expressed gene using paired analysis of before and after treatment samples. In responders, this approach revealed 256 significantly differentially expressed genes of which 72 genes were down-regulated and 184 genes were up-regulated at time of progression. Genes differentially expressed in responders revealed a shift towards a more proneural and less mesenchymal phenotype at the time of progression. These transcriptional changes were found associated to inhibition of TGF-β1.Conclusion:Bevacizumab combination treatment is associated with significant transcriptional changes in responders but not in non-responders. This suggests that non-responders progress due to intrinsic resistance while responders progress due to acquired resistance. Our data suggests that responding glioblastomas undergoes a reverse mesenchymal shift at the time of recurrence, possibly related to down-regulation of TGF-β activity.
Abstract 3254: Promotion of colon cancer invasion and metastasis via activation of Notch-Dab1-Abl-RhoGEF protein Trio
Authors: Mark Taketo
Journal: Cancer Research (2015)

Abstract We have recently identified a metastasis suppressor gene for colorectal cancer (CRC); AES/Aes which encodes an endogenous inhibitor of Notch signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here we show that one of the genes induced by Notch signaling in CRC is DAB1/Dab1. Genetic depletion of Dab1 suppresses cancer invasion and metastasis in the Notch signaling-activated mice. Dab1 is phosphorylated by Abl tyrosine kinase, which activates Abl reciprocally. Consistently, inhibition of Abl suppresses cancer invasion in mice. Furthermore, we show that one of the targets of Abl Tyr-kinase is Rac/Rho-GEF protein Trio, and that phosphorylation at its Tyr residue 2681 (pY2681) causes Rho activation in CRC cells. Its unphosphorylatable mutation Trio(Y2681F) reduces the RhoGEF activity, and inhibits invasion of CRC cells. Importantly, Trio(pY2681) correlates with significantly poorer prognosis of CRC patients after surgery. These results indicate that Trio(pY2681) is one of the downstream effects by Notch signaling activation in CRC, and can be a prognostic marker, helping determine the therapeutic modality of CRC patients. Citation Format: Mark Taketo. Promotion of colon cancer invasion and metastasis via activation of Notch-Dab1-Abl-RhoGEF protein Trio. [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 3254. doi:10.1158/1538-7445.AM2015-3254
The 46/1 Haplotype Frequency Is Not Increased in Patients of Essential Thrombocythemia with CALR Mutations
Authors: Jyh-Pyng Gau, Chih-Cheng Chen, Chia-Jen Liu, Yuan-Bin Yu, Liang-Tsai Hsiao, Jin-Hwang Liu, Po-Min Chen, Cheng-Hwai Tzeng
Journal: Blood (2014)
Abstract 4538: Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy
Authors: Sarangthem V. Devi, Yun Jae Kim, Young-Jin Lee, Kuen Hur, Byung-Heon Lee, Rang Woon Park
Journal: Cancer Research (2015)

Abstract The main objectives of drug delivery for almost all cancer therapies are to improve the therapeutic index of anticancer drugs by increasing the amount of drug delivered to the specific tumor site and decreasing its exposure to healthy tissues. Elastin like Polypeptides (ELPs) retain all the advantages of polymeric drug delivery systems, as they are composed of non-toxic and biodegradable amino acid, derived from mammalian tropoelastin. IL-4 receptors (IL-4R) are found to be highly expressed in a wide variety of human tumors and studies have reported that IL-4/IL-4R interactions amplify the expression of some anti-apoptotic proteins, so prevent drug-induced cancer cell death. Thus we have designed multivalent IL-4R targeted based macromolecular carriers, AP1-ELP polymers, in order to examine the therapeutic efficacy in delivering the therapeutic peptide (KLAKLAK)2 to tumor cells. As for the study AP1-ELP polymer, containing six IL-4R binding peptide (AP1) was conjugated with proapoptotic peptide (KLAKLAK)2 on the C-terminal site by cloning. The resultant AP1-ELP-(KLAKLAK)2 construct was successfully expressed and purified from E coli using inverse temperature cycling method. Confocal imaging verified the better cellular accumulation of AP1-ELP-(KLAKLAK)2 in IL-4R highly expressing cancer cells. The cytotoxic effect towards IL-4R highly expressing tumor cells were highly enhanced when treated with AP1-ELP-(KLAKLAK)2 compared to control. FACS analysis data confirmed the significant increase of apoptotic cells when treated with AP1-ELP-(KLAKLAK)2 compared to ELP-(KLAKLAK)2 in dose dependent manner. Ex vivo biodistridution study displayed an increase in intra-tumoral uptake and localization of FNR-675 labeled AP1-ELP-(KLAKLAK)2 than ELP-(KLAKLAK)2. Additionally, AP1-ELP-(KLAKLAK)2 significantly inhibit the tumor growth when injected intravenously in MDA-MB 231 xenograft mouse model. Thus AP1-ELP-(KLAKLAK)2 polymer enhanced apoptotic and antitumor activity against IL-4R highly expressing tumor cells suggesting the clinical potential of our polymer. Citation Format: Sarangthem V. Devi, Yun Jae Kim, Young-Jin Lee, Kuen Hur, Byung-Heon Lee, Rang Woon Park. Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2015-4538
Abstract 3305: The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response
Authors: Samantha L. Sobus, Sundaravadivel Balasubramanian, Michelle A. Romano, Graham W. Warren
Journal: Cancer Research (2015)

Abstract Tobacco use is the single largest preventable risk factor for developing cancer. Furthermore, tobacco is associated with poor therapeutic outcomes in part because its continued use has been shown to decrease the efficacy of conventional chemotherapy and/or radiotherapy (RT). Preclinical data suggests that nicotine administration decreases RT efficacy by activating the alpha-7-nicotinic acetylcholine receptor (a7-nAChR). Our study evaluated the effects of nicotine and selective a7-nAChR agonists (LY 2087101, PHA 543613, PNU 282987, and TC 1698) administration on radiotherapeutic efficacy. H460 and A549 human lung cancer cell lines were dose escalated with nicotine and the a7-nAChR agonists alone or in combination with single fraction X-ray radiation (2, 6 Gy) and cell survival was assessed by clonogenic assay. Nicotine administration and activation of a7-nAChR by LY 2087101 or PHA 543613 was found to have a radioprotective effect in both cell lines by increasing cell survival following RT. Conversely, activation of a7-nAChR by PNU 282987 or TC 1698 did not modulate radiotherapeutic response. Western blot analysis demonstrated that although all four tested a7-nAChR agonists increased phosphorylation of AKT (S473), only PHA 543613 and LY 2087101 were found to also activate mTOR (S2448). Additional clonogenic studies were performed to further examine the role of mTORC1 in governing response to RT. Inhibition of mTORC1 by rapamycin alone sensitized both A549 and H460 cells to the effect of RT. Interestingly, rapamycin treatment was sufficient to block the radioprotective effects of nicotine, PHA 543613, and LY 2087101 in A549 cells, however, in H460 cells rapamycin did not restore radiotherapeutic efficacy. Moreover, examination of Deptor, a key component of mTOR complexes shown to be associated with RT response, demonstrated that a7-nAChR activation by nicotine, PHA 543613, or LY 2087101 increased Deptor degradation in A549 cells, while a7-nAChR activation decreased Deptor degradation in H460 cells. These observations suggest that differences in the regulation of Deptor level may contribute to the variation in both rapamycin sensitivity and restoration of therapeutic efficacy to RT between H460 and A549 cell lines. Additional studies will be necessary to further elucidate the role of the mTOR complexes in mediating a7-nAChR induced modulation of response to RT. Citation Format: Samantha L. Sobus, Sundaravadivel Balasubramanian, Michelle A. Romano, Graham W. Warren. The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response. [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 3305. doi:10.1158/1538-7445.AM2015-3305
Fluorescence In Situ Hybridisation (FISH) To Reveal Isochromosome 7q, i(7)(q10), in Hepatosplenic T-Cell Lymphoma (HSTCL).
Authors: Paolo Bernasconi, Irene Dambruoso, Marina Boni, Paola Maria Cavigliano, Ilaria Giardini, Rita Zappatore, Silvia Calatroni, Barbara Rocca, Cesare Astori, Carlo Castagnola, Mario Lazzarino
Journal: Blood (2006)
Abstract 3378: Discoidin domain receptor 2 differentially controls HT-1080 cell proliferation in young-adult and old type I collagen 3D matrices
Authors: Charles Saby, Roselyne Garnotel, Hassan El Btaouri, Laurence Van Gulick, Pierre Jeannesson, Hamid Morjani
Journal: Cancer Research (2015)

Abstract Type I collagen plays a key role in tumor proliferation, adhesion and migration. We have recently demonstrated that this fibrillar and life-long protein undergoes detrimental changes in biochemical and biomechanical properties during aging (1). In addition to a high Advanced Glycation End-products (AGE) and cross-links content, old collagen exhibits a significant loss in fibrillar properties. In this study, we analyzed the effect of collagen aging on human HT-1080 fibrosarcoma cell proliferation in 3D matrix model. For this, type I collagen was extracted from tail tendons of young-adult (2 months) and old (2 years) rats. In 3D matrix, the rate of HT-1080 cell growth was significantly lower in young-adult collagen. This was accompanied by a down-regulation of ERK1/2 phosphorylation and an increase in the cyclin-dependent kinase inhibitor p21 expression. Blocking antibodies and siRNA strategy against β1 integrin and AGEs receptor (RAGE) did not increase cell growth in young-adult collagen. Accumulating evidence suggest that Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase with the unique ability to be activated by fibrillar collagen. To determine whether differential DDR2 responses are elicited by the two collagens, DDR2 was immunoprecipitated from cell lysates, and its phosphorylated form was detected by immunoblotting. DDR2 phosphorylation level was increased in young-adult collagen. This was accompanied by an increase in the tyrosine phosphatase SHP2 phosphorylation, the primary target of DDR2. Interestingly, the DDR2 inhibitor nilotinib was able to restore cell proliferation in young-adult collagen. In addition to an increase in ERK1/2 phosphorylation, nilotinib decreased SHP2 phosphorylation and p21 expression. Taken together, these data show that age-associated changes of type I collagen organization, especially fibrillar properties, are critical for tumor cell proliferation control by DDR2. References: (1) Wilson SL et al. FASEB J. 2014 28(11):14-25 Citation Format: Charles Saby, Roselyne Garnotel, Hassan El Btaouri, Laurence Van Gulick, Pierre Jeannesson, Hamid Morjani. Discoidin domain receptor 2 differentially controls HT-1080 cell proliferation in young-adult and old type I collagen 3D matrices. [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 3378. doi:10.1158/1538-7445.AM2015-3378
Abstract LB-125: The identification of FOXA1/ERα pathway modulators for the treatment of hormone-based therapy resistant breast cancer
Authors: jon roffey, Aurore Lejeune, Michelle Barnard, Julie Stock, Ai Ching Wong, Jenny McKelvie, Kelly Holmes, Jason Carroll, Stephen Myatt
Journal: Cancer Research (2015)

Abstract Estrogen receptor alpha (ERα) is expressed in ∼75% of breast cancers where it binds and regulates specific target genes which drive cancer cell proliferation. Hormone-based treatments such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors prevent estrogen signalling through the ERα, but in many cases resistance to these therapies develops. FOXA1 is a pioneer factor for ERα that is required to facilitate ERα binding to its target genes and its expression is considered to be a defining gene that characterizes ERα positive luminal breast cancers. Here we show that FOXA1 is an essential gene in ERα positive, tamoxifen resistant and aromatase-resistant breast cancer cell lines suggesting inhibitors that target the FOXA1/ERα pathway could have broad utility in these settings. To this end we performed a cell-based screen to identify novel small molecule regulators of FOXA1/ERα pathway activity. Our novel cell-based assay allowed us to screen over 180, 000 discrete compounds in a high through-put manner. Counter screens and phenotypic profiling in FOXA1 positive and negative breast cancer cell lines were used to remove non-specific compounds and direct ERα modulators. Second batches of confirmed actives were profiled through the screening cascade and by using ChIP assays we have observed a reduction in FOXA1 binding at the chromatin that is commensurate with a similar loss of ERα binding, demonstrating for the first time pharmacological modulation of FOXA1/ERα occupancy at the chromatin level. Citation Format: jon roffey, Aurore Lejeune, Michelle Barnard, Julie Stock, Ai Ching Wong, Jenny McKelvie, Kelly Holmes, Jason Carroll, Stephen Myatt. The identification of FOXA1/ERα pathway modulators for the treatment of hormone-based therapy resistant breast 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-125. doi:10.1158/1538-7445.AM2015-LB-125
Quercetin‐Based Modified Porous Silicon Nanoparticles for Enhanced Inhibition of Doxorubicin‐Resistant Cancer Cells
Authors: Zehua Liu, Vimalkumar Balasubramanian, Chinmay Bhat, Mikko Vahermo, Ermei Mäkilä, Marianna Kemell, Flavia Fontana, Agne· Janoniene, Vilma Petrikaite, Jarno Salonen, Jari Yli‐Kauhaluoma, Jouni Hirvonen, Hongbo Zhang, Hélder A. Santos
Journal: Advanced Healthcare Materials (2016)

One of the most challenging obstacles in nanoparticle's surface modification is to achieve the concept that one ligand can accomplish multiple purposes. Upon such consideration, 3‐aminopropoxy‐linked quercetin (AmQu), a derivative of a natural flavonoid inspired by the structure of dopamine, is designed and subsequently used to modify the surface of thermally hydrocarbonized porous silicon (PSi) nanoparticles. This nanosystem inherits several advanced properties in a single carrier, including promoted anticancer efficiency, multiple drug resistance (MDR) reversing, stimuli‐responsive drug release, drug release monitoring, and enhanced particle−cell interactions. The anticancer drug doxorubicin (DOX) is efficiently loaded into this nanosystem and released in a pH‐dependent manner. AmQu also effectively quenches the fluorescence of the loaded DOX, thereby allowing the use of the nanosystem for monitoring the intracellular drug release. Furthermore, a synergistic effect with the presence of AmQu is observed in both normal MCF‐7 and DOX‐resistant MCF‐7 breast cancer cells. Due to the similar structure as dopamine, AmQu may facilitate both the interaction and internalization of PSi into the cells. Overall, this PSi‐based platform exhibits remarkable superiority in both multifunctionality and anticancer efficiency, making this nanovector a promising system for anti‐MDR cancer treatment.
Acute kidney injury in liver cirrhosis: new definition and application
Authors: Florence Wong
Journal: Clinical and Molecular Hepatology (2016)

The traditional diagnostic criteria of renal dysfunction in cirrhosis are a 50% increase in serum creatinine (SCr) with a final value above 1.5 mg/dL. This means that patients with milder degrees of renal dysfunction are not being diagnosed, and therefore not offered timely treatment. The International Ascites Club in 2015 adapted the term acute kidney injury (AKI) to represent acute renal dysfunction in cirrhosis, and defined it by an increase in SCr of 0.3 mg/dL (26.4 µmoL/L) in <48 hours, or a 50% increase in SCr from a baseline within ≤3 months. The severity of AKI is described by stages, with stage 1 represented by these minimal changes, while stages 2 and 3 AKI by 2-fold and 3-fold increases in SCr respectively. Hepatorenal syndrome (HRS), renamed AKI-HRS, is defined by stage 2 or 3 AKI that fulfils all other diagnostic criteria of HRS. Various studies in the past few years have indicated that these new diagnostic criteria are valid in the prediction of prognosis for patients with cirrhosis and AKI. The future in AKI diagnosis may include further refinements such as inclusion of biomarkers that can identify susceptibility for AKI, differentiating the various prototypes of AKI, or track its progression. Keywords: Hepatorenal syndrome; Ascites; Renal dysfunction; Treatment
BONE Marrow Stromal CELL Paracrine Factors from PMF Patients, but NOT Healthy Donors, Protect JAK2V617F CELLS from Ruxotinib-Induced Apoptosis
Authors: Taghi Manshouri, Zeev Estrov, Liza Knez, Ying Zhang, Ksenija Bozinovic, Vilma Dembitz, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Blood (2014)
An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity in Vitro and in Vivo against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma
Authors: Eugene A. Zhukovsky, Holly Horton, Matthias Peipp, Erik Pong, Matthew Bernett, Sher Karki, John Richards, Seung Chu, Roland Repp, John Desjarlais
Journal: Blood (2008)
Clinical Outcomes of Haploidentical Donor Compared with Unrelated and HLA-Matched Related Donor Hematopoietic Stem Cell Transplantation for Hematologic Malignancies
Authors: Yi Luo, Yamin Tan, Xiaoyu Lai, Weiyan Zheng, Jimin Shi, Gaofeng Zheng, He Huang
Journal: Blood (2012)
127. Lentiviral Protein Transduction for Tailored Genome Editing and Site-Directed Gene Insertion
Authors: Yujia Cai, Rasmus O. Bak, Anders Laustsen, Yan Zhou, Chenglong Sun, Yonglun Luo, Martin R. Jakobsen, Jacob G. Mikkelsen
Journal: Molecular Therapy (2016)

Therapeutic use of site-directed endonucleases relies on safe and effective cellular delivery, preferentially resulting in short-term enzymatic activity. Based on the packaging of Gag/GagPol-fused heterologous proteins into VSV-G-pseudotyped lentivirus-derived particles, we have established lentiviral protein transduction for delivery of DNA transposases and custom-made endonucleases. Up to 24% of targeted CCR5 and AAVS1 alleles were disrupted in primary cells, including normal human dermal fibroblasts and primary keratinocytes, exposed to lentiviral particles loaded with zinc-finger nucleases (ZFNs). By exposing human 293 cells to 'all-in-one' integrase-defective lentiviral vectors (IDLVs) containing a complete gene repair kit consisting of ZFNs and viral RNA carrying the donor sequence for homology-directed repair, correction of genomic mutations was obtained in more than 8% of treated cells. As shown by confocal microscopy, ZFN proteins were abundant within transduced cells one hour after initial virus exposure, but were short-lived and gone after 24 hours. In accordance, under conditions supporting comparable CCR5 indel rates, disruption of the nearby CCR2 off-target site was reduced by lentiviral delivery of ZFNs targeting CCR5 relative to a conventional transfection-based approach. As biased and uncontrolled integration into genes remains a key challenge for gene therapies based on lentiviral vector technologies, we engineered ZFN-loaded IDLVs with the capacity to insert transgenes into the human CCR5 and AAVS1 loci by a homology-driven mechanism. Targeted gene integration into safe genomic loci was observed in human cell lines (85% of analyzed clones) and in human stem cells, including CD34+ hematopoietic progenitors and induced pluripotent stem cells (iPSCs). Notably, targeted transgene insertion into safe harbors was identified in all of 23 analyzed iPSC clones. Altogether, our findings generate a new platform for targeted genome engineering based on lentiviral delivery of complete gene repair or gene insertion kits.