tbuckley/cabot-search huggingface dataset:
Abstract 4414: RhoA activation in diffuse type gastric adenocarcinoma promotes cancer stem cell phenotypes including chemotherapy resistance
Authors: Changhwan Yoon, Soo-Jeong Cho, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon
Journal: Cancer Research (2015)

Abstract Introduction: The diffuse type of gastric adenocarcinoma (GA) was recently found to frequently harbor activating mutations in RHOA. RhoA is a member of the small GTPase-Ras-like proteins which are involved in cell signaling for cell migration and cell cycle. Methods: RhoA activity and inhibition was examined in diffuse GA cell lines grown as spheroids (i.e. cancer stem cell conditions) and as monolayers in various in vitro assays. RhoA knockdown combined with chemotherapy was examined in a mouse xenograft model. Results: RhoA activity was much higher in diffuse GA cell lines MKN-45 and SNU-668 compared to intestinal GA cell lines NCI-N87 and AGS. RhoA activity was further increased in diffuse GA cells when grown as spheroids rather than as monolayers. RhoA inhibition with shRNA or the RhoA inhibitor Rhosin decreased spheroid formation and deceased expression of the stem cell transcription factor, Sox2. Diffuse GA cells when grown as spheroids had significantly greater migration, invasion, and anchorage-independent growth, and these properties could all be blocked with RhoA shRNA or Rhosin. Diffuse GA spheroid cells (compared to monolayer cells) were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with RhoA inhibition. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, RhoA shRNA by 60%, and the combination by 83%. Clinical tumor samples of diffuse GA are currently being analyzed for RhoA expression and correlated with extent of disease and response to chemotherapy. Conclusions: RhoA signaling is upregulated in diffuse GA cells grown as spheroids and promotes malignant transformation phenotypes such as migration and invasion. RhoA inhibition can reverse chemotherapy resistance in GC spheroid cells and in tumor xenografts, and thus the RhoA pathway is a promising new target of therapy for diffuse GA. Citation Format: Changhwan Yoon, Soo-Jeong Cho, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon. RhoA activation in diffuse type gastric adenocarcinoma promotes cancer stem cell phenotypes including chemotherapy resistance. [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 4414. doi:10.1158/1538-7445.AM2015-4414
BKT140 Is a Novel CXCR4 Antagonist with Stem Cell Mobilization and Antimyeloma Effects: An Open-Label First Human Trial In Patients with Multiple Myeloma Undergoing Stem Cell Mobilization for Autologous Transplantation
Authors: Arnon Nagler, Avichai Shimoni, Irit Avivi, Jacob M. Rowe, Katia Beider, Izhar Hardan, Michal Abraham, Hanna Wald, Eithan Galun, Howard Laurence Shaw, Orly Eizenberg, Amnon Peled
Journal: Blood (2010)
Abstract IA17: The global phospho-proteome of K-Ras mutant cells and tissues
Authors: Kevin Haigis
Journal: Cancer Research (2016)

Abstract K-Ras is the most commonly mutated oncogene in cancer and it plays a predominant role in the pathogenesis of cancers of the pancreas, colon, and lung. Mutationally activated K-Ras influences cellular behaviors through broad and complex effects on downstream signal transduction pathways. In an effort to understand the molecular mechanisms underlying the oncogenic properties of mutant forms of K-Ras, we are using mass spectroscopy (MS) to quantify proteome-wide changes in protein phosphorylation in primary mouse tissues that are engineered to express mutant forms of K-Ras. In total, we have obtained relative quantification of 5,936 and 11,455 phospho-peptides from mouse pancreas and colon of varying K-Ras genotype. The dataset paints a complex picture of signaling downstream of K-Ras, as phosphorylation of many proteins in known Ras effector pathways (i.e. MAPK and PI3K) are unaffected or down-regulated by mutationally activated K-Ras. Moreover, we have found that different activating K-Ras alleles often have polar effects on the phosphorylation state of a given downstream protein. The biological significance of any given phosphorylation change in a large dataset such as this is often difficult to interpret, since the vast majority of quantified sites have no functional annotation. To combat this issue, we developed phospho-site set enrichment analysis (PSSEA), a computational tool that identifies kinases that are activated in a given sample based on the representation of known substrates in the phospho-MS dataset. PSSEA revealed, for example, that casein kinase 2 (Csnk2a1) is selectively activated by K-RasG12D in the pancreas, but not in the colon. Overall, this study provides an unprecedented view of K-Ras signaling on a global scale and reveals a variety of novel insights into the signal transduction properties of different K-Ras alleles. Ultimately, systems-level and bioinformatic analyses of these data will reveal new therapeutic targets for cancers expressing mutant forms of K-Ras. Citation Format: Kevin Haigis.{Authors}. The global phospho-proteome of K-Ras mutant cells and tissues. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA17.
Impaired Histone H3 Lysine 9 Methylation Accelerates Ras-Driven Lymphomagenesis by Disabling Cellular Senescence.
Authors: Melanie Braig, Christoph Loddenkemper, Antoine H.F.M. Peters, Harald Stein, Bernd Dorken, Thomas Jenuwein, Clemens A. Schmitt
Journal: Blood (2004)
Growth rate of small pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: results from an endoscopic ultrasound based cohort study
Authors: Wouter Kappelle, Gerlof Valk, Max Leenders, Leon Moons, Auke Bogte, Peter Siersema, Frank Vleggaar
Journal: Endoscopy (2016)

<b>Background and aims</b> In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound (EUS) is used for identification and follow-up of pancreatic neuroendocrine tumors (PNETs). The role of EUS in surveillance of small ( < 20 mm) PNETs is unclear, mostly because the natural course of these lesions is largely unknown. We aimed to determine annual growth and incidence rate of small PNETs in patients with MEN1 using EUS-based surveillance. <b>Patients and methods</b> Linear array EUS procedures in patients with MEN1 between 2002 and 2015 were identified. Number, size, and location of PNETs were recorded. Annual growth of PNETs < 20 mm identified at the initial EUS ("prevalent" PNETs) and during follow-up ("incident" PNETs) was calculated using mixed model linear regression analysis. <b>Results</b> A total of 54 patients were identified and 38 patients were included. In all, 226 PNETs were identified (median size 5.0 mm, interquartile range 3.7 – 7.5) of which 124 (55 %) were prevalent and 102 (45 %) were incident PNETs. Annual incidence rate was 0.79 PNETs/year (95 % confidence interval [CI] 0.73 to 0.87). Overall growth rate was 0.10 mm/year (95 %CI 0.02 to 0.19; <i>P</i> = 0.01); PNETs < 10 mm (n = 198) did not grow (<i>P</i> = 0.23), whereas PNETs ≥ 10 mm (n = 28) grew 0.44 mm/year (95 %CI 0.10 to 0.78; <i>P</i> = 0.01). Prevalent PNETs grew 0.21 mm/year (95 %CI 0.10 – 0.32; <i>P</i> < 0.001), whereas incident PNETs did not grow (<i>P</i> = 0.26). <b>Conclusions</b> The annual growth rate of small, solid PNETs in patients with MEN1 is lower than previously thought. Surveillance intervals could probably be prolonged without compromising safety.
Variants in <i>WFS1</i> and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity
Authors: Heather E. Wheeler, Eric R. Gamazon, Robert D. Frisina, Carlos Perez-Cervantes, Omar El Charif, Brandon Mapes, Sophie D. Fossa, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Christian Kollmannsberger, Jeri Kim, Taisei Mushiroda, Michiaki Kubo, Shirin Ardeshir-Rouhani-Fard, Lawrence H. Einhorn, Nancy J. Cox, M. Eileen Dolan, Lois B. Travis
Journal: Clinical Cancer Research (2016)

Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10-8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325-33. ©2016 AACR.
Comparison of Differential Gene Expression Profiles of Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide with the Profile of An Arsenic Trioxide Resistant NB4 Cell Line.
Authors: Ezhilarasi Chendamarai, Ramachandran Shaji, Auro Viswabandya, Biju George, Alok Srivastava, Mammen Chandy, Vikram Mathews
Journal: Blood (2009)
462. Automated Manufacturing Process for the Production of Genetically Modified Lymphocytes
Authors: Simona La Seta Catamancio, Manuela Cota, Ralitsa Arnaudova, Patrizia Mangia, Paolo Morandi, Michele Manfredini, Simona Rovetta, Sergio Fracchia, Giuliana Vallanti, Gian-Paolo Rizzardi, Catia Traversari
Journal: Molecular Therapy (2015)

The MM-TK is a medicinal product constituted of T lymphocytes ex vivo genetically modified with the γ retroviral vector SFCMM-3 Mut2 #48 to express a mutated form of the Herpes Simplex Virus Thymidine kinase (HSV-TK Mut2) and a truncated form of the human Low affinity Nerve Growth Factor Receptor (ΔLNGFR) genes. It has development as adjunctive therapy in leukaemia patients or undergone bone marrow transplantation. The current manufacturing process is performed following semi-automated procedure using instrument and tubing set not marketing compliant. In order to optimize this and to standardize cellular therapeutic production for clinical trial and for the market, MolMed have strengthened an alliance with Miltenyi Biotec for tailoring of CliniMACS Prodigy platform for MM-TK DS manufacturing. A closed and automated cell process was developed using the new device with a specific software designed in order to manufacture a robust, safe and consistent product. The manufacturing process essentially consists in the stimulation of a large number of PBMCs (about 3×109 cells) isolated from an haploidentical donor, with anti-CD3 monoclonal antibody and IL-2, transduction of the stimulated cells with the SFCMM-3 Mut2 #48 retroviral vector in RetroNectin® coated bags and immunoselection of positively transduced cells using the CD271-LS Microbeads reagent (Miltenyi Biotec). Selected TK cells are then further expanded for 7 days before final formulation in freezing medium. The whole manufacturing process lasts 13 days. The following steps have been automated: cell concentration and cell washing at different manipulation steps and immunomagnetic selection of the transduced cells. Four development full-scale runs demonstrate that automated cell processing for the genetic manipulation of T lymphocytes can be performed in the closed- and automated-system designed by MolMed, reaching good results for all in-process parameters evaluated: cell recovery of 80-90%; cell viability more than 80% at each step; total process yield of 72%. The DS/DP product has been evaluated for the quality attributes as product and process related impurities (CD14% + CD16% + CD19% and residual retronectin, residual anti-CD3, residual CD271 microbeads) and potency of the product (ΔLNGFR expression; sensitivity to Ganciclovir; Vector Copy Number; immunophenotype as CD3%, CD4%, CD8%, CD45%, CD25, CD69, HLA-DR, CD95; CD45RA and CD62L). The results will support the discussion with Regulatory Autorities and permit the introduction of the new optimized closed manufacturing process in the late phase of the clinical trial and for the market.
466. Manufacturing Solutions for Robust Cell Therapy Expansion and Harvest
Authors: Julie Murrell, Samantha Luther, Tristan Lawson, Anjali Verma, Susan Rigby, Sandhya Punreddy, Manjula Aysola, Tiffany Hood, Daniel Kehoe, Aletta Schnitzler, Martha Rook
Journal: Molecular Therapy (2016)

The long-term view of regenerative medicine therapies predicts an increased need for expansion solutions that ease scalability, utilize animal origin-free materials and are compatible with limited downstream processing steps. As more cell therapeutics progress through clinical testing, current in vitro culture methods are proving cumbersome to scale and lack robustness. Moreover, high quality animal origin-free reagents and downstream processing devices support the future implementation of large scale manufacturing solutions that will be required following clinical success. Here, we describe the implementation of single use bioreactors and high quality media for expansion of cell therapies. We include examples from allogeneic mesenchymal stem cells and autologous T cells. The presentation will review solutions addressing animal origin-free expansion of cells within the context of different upstream process development steps as well as scaling and downstream processing with good cell quality, high recovery, high viability and good activity. Start to finish solutions for expansion and harvest, including high quality reagents, are key enabling technologies for success in commercializing cell therapies.
Long-Term Assessment of Dasatinib-Induced Pulmonary Arterial Hypertension in Chronic Myeloid Leukemia
Authors: Jee Hyun Kong, Young-Woo Jeon, Sung-Eun Lee, Soo Young Choi, Soo-Hyun Kim, Yun Jeong Oh, Jin-Eok Park, Hye-Rim Jeon, Eun-Jung Jang, Suk Joong Oh, Dong-Wook Kim
Journal: Blood (2014)
QLIF-09. A FOCUS ON THE PSYCHOSOCIAL NEEDS OF OLDER BRAIN TUMOR PATIENTS
Authors: Jennifer Pham, Cheryl Abe, Hye Hyun Bahng, Jazmin Sevilla, Nanette Fong, Albert Lai, Timothy Cloughesy, Phioanh Nghiemphu
Journal: Neuro-Oncology (2016)

Much of the current research on brain tumor patients is focused on the clinical aspect. Only a few studies have explored the unmet psychosocial needs of brain tumor patients. Furthermore these studies are not targeted towards the older age group, even though older adults are shown to have the highest incidence of brain tumors and the lowest survival rates. The present study evaluated whether the need for psychosocial services of older brain tumor patients would differ from the rest of the brain tumor patients. A total of 490 brain tumor patients completed a questionnaire comprising of psychosocial topics that are of interest to the patient. Patients were given this questionnaire at each clinical visit over a 9-month period. Of those 490 brain tumor patients, 89 patients were over the age of 65. Patients who are of age 65 and older reported a higher need of discussing their goals of treatment (35% vs 27% for younger patients), quality of life (21% vs 13%), and anxiety (15% vs 9%). Older brain tumor patients also needed more help with home care (13% vs 5% for younger patients), transportation (6% vs 4%), and advance healthcare directives (4% vs 2%). These results demonstrate that some psychosocial services are of higher need and interest to older brain tumor patients than to patients under the age of 65. Future studies may look at the extent of these needs and utilize these findings to provide better targeted care and adequate support for older patients with brain tumors.
Thyroid metastases from clear cell renal cell carcinoma: A case report.
Authors: M. Ricci, L. Buci, M. Gaudio, C. Milandri
Journal: Journal of Clinical Oncology (2011)

e15066 Background: Renal cell carcinoma can metastasize to unusual sites such as the thyroid gland. Such cases typically present with a unilateral painless cold nodule at scintiscan, hypoechogenic at ultrasonography, with final diagnosis made by fine-needle aspiration. Methods: An 87-year-old woman with clear cell renal cell carcinoma was treated by radical nefrectomy in April 2003. She relapsed in 2009 in the abdomen and underwent resection of the large, symptomatic metastasis. Around the same time bilateral lung lesions appeared. The patient was subsequently treated with sunitinib 50 mg daily in cycles of 4 weeks with a two-week interval. The dose was reduced to 37.5 mg because of bone marrow toxicity. After 17 months of treatment the lung metastases were stable but bilateral thyroid nodules were detected. Results: Thyroid function tests were normal. Ultrasound-guided biopsy found atypical cell aggregates with clear cytoplasm and positivity for CD10 and vimentin, compatible with clear cell renal cell carcinoma. The patient began treatment with everolimus in January 2011. Conclusions: Although thyroid metastases from clear cell renal cell carcinoma are extremely rare and generally only appear, along with other extra-thyroid metastases, many years after the primary diagnosis, they must be taken into consideration in patients with a long history of renal carcinoma.
Epigenetic therapy with valproic acid, an HDAC inhibitor, in refractory/relapsed non-Hodgkin lymphoma (NHL) and Hodgkin disease.
Authors: M. Cotto, F. Cabanillas, G. Garcia-Manero, H. Yang, M. Bruno, O. A. Pavia, E. Rivera, I. Liboy, M. Tirado-Gomez
Journal: Journal of Clinical Oncology (2011)

8056 Background: Valproic Acid (VPA) functions as a histone deacetylase (HDAC) inhibitor. HDAC inhibition can cause growth arrest of cells, and can induce differentiation in various models of cancer cells in vivo and in vitro. VPA represents an interesting potential antineoplastic agent but very limited data are available on its activity. We decided to investigate VPA's activity in patients with refractory lymphoma in view of its minimal toxicity and low cost. Methods: The study was designed using the Simon two-stage approach for phase II clinical trials. First stage, 9 patients of the two major histologic categories were included. Categories were: 1) indolent and 2) aggressive NHL plus Hodgkin disease (HD). If no responses were observed in either category, the study was to be stopped. However, if one response were observed in any of the 2 categories, we would proceed to second stage. Fourteen previously treated pts with relapsed/refractory HD and NHL have been entered. They started VPA at 30 mg/kg/day. Adjustments were done to keep VPA levels between 50-100 μg/mL. Blood for hyperacetylation studies was collected from 9 patients on days 0, 7, and 21. Results: Of 14 pts, 6 had HD, 5 diffuse large B cell (DLCL-B) 2 were transformed follicular, and 1 follicular. There were 4/14 (29%) responses, all partial remissions (PR), and 3 stable disease. Pts were heavily pretreated with median number of 3 relapses. Responses according to histology: 2/6 HD, 0/5 DLCL-B, 1/2 transformed follicular, 1/1 follicular NHL. Progression free survival for PRs was: 2 mosfor HD, 9 mo for transformed follicular, and 7+ mo for follicular NHL. Stable disease lasted 6, 4 and 2 months. Data on acetylation studies in peripheral blood revealed 4/9 with evidence of HDAC inhibition on day 7 and 3/5 on day 21. Of 6 with evidence of HDAC inhibition either on day 7 or day 21, 4 responded to therapy. Conclusions: In view of activity in both histologic categories study has proceeded to 2nd stage. VPA has preliminary activity in these heavily pretreated pts, including HD, follicular NHL and transformed follicular.
Bortezomib in Combination with Bendamustine and Prednisone in the Treatment of Patients with Refractory/Relapsed Multiple Myeloma.
Authors: Wolfram Poenisch, Malvina Bourgeois, Song-Yau Wang, Simone Heyn, Nadja Jaekel, Leanthe Braunert, Robert Rohrberg, Hans Juergen Hurtz, Franz Albert Hoffmann, Andreas Schwarzer, Cornelia Becker, Haifa Al Ali, Dietger W. Niederwieser
Journal: Blood (2007)
Survival Outcomes of Adults with Acute Myeloid Leukemia – A Study of Native American, Hispanic, and Non-Hispanic Whites Treated In New Mexico (1986 to 2006)
Authors: Nancy Rivera, Beeling Armijo, Dulcinea Quintana, Maryam Abdul-Jaleel, Sang-Joon Lee, Charles Wiggins, Edward Libby
Journal: Blood (2010)
Prediction of Fetal Hemoglobin in Sickle Cell Anemia Using a Genetic Risk Score
Authors: Jacqueline N Milton, Paola Sebastiani, Clinton T. Baldwin, Efthymia Melista, Victor R. Gordeuk, Mehdi Nouraie, Gregory J. Kato, Caterina Minniti, James G. Taylor, Andrew Campbell, Lori Luchtman-Jones, Sohail R. Rana, Oswaldo L Castro, Yingze Zhang, Mark T Gladwin, Martin H. Steinberg
Journal: Blood (2012)
Association between sleep apnoea and pulmonary hypertension in Kyrgyz highlanders
Authors: Tsogyal D. Latshang, Michael Furian, Sayaka S. Aeschbacher, Silvia Ulrich, Batyr Osmonov, Erkin M. Mirrakhimov, Jainagul Isakova, Almaz A. Aldashev, Talant M. Sooronbaev, Konrad E. Bloch
Journal: European Respiratory Journal (2016)

This case–control study evaluates a possible association between high altitude pulmonary hypertension (HAPH) and sleep apnoea in people living at high altitude. Ninety highlanders living at altitudes &gt;2500 m without excessive erythrocytosis and with normal spirometry were studied at 3250 m (Aksay, Kyrgyzstan); 34 healthy lowlanders living below 800 m were studied at 760 m (Bishkek, Kyrgyzstan). Echocardiography, polysomnography and other outcomes were assessed. Thirty-six highlanders with elevated mean pulmonary artery pressure (mPAP) &gt;30 mmHg (31–42 mmHg by echocardiography) were designated as HAPH+. Their data were compared to that of 54 healthy highlanders (HH, mPAP 13–28 mmHg) and 34 healthy lowlanders (LL, mPAP 8–24 mmHg). The HAPH+ group (median age 52 years (interquartile range 47–59) had a higher apnoea–hypopnoea index (AHI) of 33.8 events·h −1 (26.9–54.6) and spent a greater percentage of the night-time with an oxygen saturation &lt;90% (T&lt;90; 78% (61–89)) than the HH group (median age 39 years (32–48), AHI 9.0 events·h −1 (3.6–16), T&lt;90 33% (10–69)) and the LL group (median age 40 years (30–47), AHI 4.3 events·h −1 (1.4–12.6), T&lt;90 0% (0–0)); p&lt;0.007 for AHI and T&lt;90, respectively, in HAPH+ versus others. In highlanders, multivariable regression analysis confirmed an independent association between mPAP and both AHI and T&lt;90, when controlled for age, gender and body mass index. Pulmonary hypertension in highlanders is associated with sleep apnoea and hypoxaemia even when adjusted for age, gender and body mass index, suggesting pathophysiologic interactions between pulmonary haemodynamics and sleep apnoea.