tbuckley/cabot-search huggingface dataset:
Abstract 1127: KIT/D816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma
Authors: Bengt Phung, Julhash U. Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R. Goding, Göran Jönsson, Jesper V. Olsen, Eiríkur Steingrímsson, Lars Rönnstrand
Journal: Cancer Research (2016)

Abstract The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of the microphthalmia-associated transcription factor (MITF) through a triple protein complex formation between KIT, MITF and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell cycle progression, suppression of senescence, survival and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells become hypersensitive to SRC inhibitors. We have therefore delineated the mechanism behind the oncogenic effects of KITD816V in melanoma and provide a rationale for testing SRC family kinase inhibitors to treat KITD816V-transformed melanomas. Citation Format: Bengt Phung, Julhash U. Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R. Goding, Göran Jönsson, Jesper V. Olsen, Eiríkur Steingrímsson, Lars Rönnstrand. KIT/D816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma. [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 1127.
A randomized, double-blind phase 2 study of sipuleucel-T followed by indoximod or placebo in the treatment of patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.
Authors: Gautam Gopalji Jha, Jeffrey S Miller
Journal: Journal of Clinical Oncology (2014)

TPS5111 Background: Vaccine development is complicated by tumor induced immune tolerance, a phenomenon in which the immune system identifies tumor antigens as “self” and allows immune evasion and subsequent sparing of the tumor to occur. This local and possibly systemic immune-suppression is primarily mediated by the inhibitory regulatory T cells (Tregs), which dominantly inhibit other T cells. Vaccine therapy is limited by this anergy and immunosuppressive microenvironment. Although sipuleucel-T has overcome this in part by its ex-vivo sensitization, Treg depletion or interfering with Treg function will likely potentiate its activity. Indoleamine 2,3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO pathway that degrades tryptophan and promotes peripheral immune tolerance by T cell inhibition and conversion of naïve T cells to Tregs. We hypothesize that targeting the IDO pathway by indoximod (1-methyl tryptophan; 1-MT) will inhibit Treg and abrogate tumor-mediated immunosuppression permitting a robust and possibly more sustained immune response to sipuleucel-T. Primary Objective: To assess the augmentation of immune response to sipuleucel-T measured at 14 weeks from first leukapheresis, in response to indoximod or placebo therapy. Secondary Objectives: To assess safety, clinical efficacy (PFS, OS) and HR-QOL. Methods: Phase 2 investigator initiated multi-center, randomized, double-blind, placebo-controlled trial. Patients will be treated with indoximod or placebo for a period up to 6 months starting a day after completion sipuleucel-T therapy. Research-related correlatives will include serial blood sampling for immune monitoring and an optional prostate or metastatic site biopsy at enrollment and at week 14. Immune monitoring will include measurements of T cell subsets, Tregs, NK cell function, PA2024-specific response, and IDO pathway inhibition. Major eligibility: Patients will be eligible for sipuleucel-T therapy as per phase III IMPACT trial inclusion criteria (Kantoff PW, NEJM 2010). Sample size and accrual: Study is open and actively recruiting, n=50 patients. Clinical trial information: NCT01560923.
Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression
Authors: W I Gonsalves, S V Rajkumar, A Dispenzieri, D Dingli, M M Timm, W G Morice, M Q Lacy, F K Buadi, R S Go, N Leung, P Kapoor, S R Hayman, J A Lust, S J Russell, S R Zeldenrust, L Hwa, T V Kourelis, R A Kyle, M A Gertz, S K Kumar
Journal: Leukemia (2016)
Abstract 1510: Subtype-specific cancer driver gene detection improves sensitivity to detect drivers
Authors: Yao Fu, Aparna Chhibber, Narges Bani-Asadi, Hugo YK Lam.
Journal: Cancer Research (2016)

Abstract Identifying cancer driver mutations is a crucial step toward understanding the underlying mechanisms of oncogenesis. However, driver gene detection is complicated, considering the inherent complexity and heterogeneity of cancer.The past decade has seen the large-scale application of next-generation sequencing technologies (NGS) in cancer genomics, and many methods have been published utilizing NGS to detect novel oncogenic drivers. However, the low concordance across methods raises the concern about false positives and negatives in those findings. In particular, proper modeling of the background mutation profile (known to be affected by multiple factors) is critical to improving precision and recall in driver detection. Though intra-sample heterogeneity in the background mutation profile is considered to some extent in multiple methods, most computational driver detection methods assume a homogeneous mutational landscape across cancer samples. With more and more subtypes being discovered in various cancers, the assumption is largely untenable. In this study, we present a driver gene detection framework taking into account the heterogeneous mutational context in a cancer cohort. Our approach improves sensitivity to detect drivers by first pre-selecting a more uniform sample subset to apply driver detection algorithms. We combine this method with enhancements to an existing ensemble approach that combines methods with different assumptions about the characteristics of driver mutations (recurrence across samples, functional impact bias and positional clustering). We apply this combined approach to ∼750 breast invasive carcinoma samples from The Cancer Genome Atlas. In this dataset, genes identified by our approach show higher enrichment in known cancer driver genes compared to other methods, and the subtype-driven method identifies additional potential drivers that are missing in overall analysis. Citation Format: Yao Fu, Aparna Chhibber, Narges Bani-Asadi, Hugo YK Lam. Subtype-specific cancer driver gene detection improves sensitivity to detect drivers. [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 1510.
Abstract 4659: Folic acid-metabolizing enzymes regulate 5-fluorouracil anticancer activity on colorectal cancer cell lines
Authors: Hiroshi Tsukihara, Kenta Tsunekuni, Teiji Takechi
Journal: Cancer Research (2016)

Abstract Background: In colorectal cancer chemotherapy, the current standard of care includes 5-fluorouracil (5-FU) and leucovorin (LV) combination therapy. To understand the role of folic acid-metabolizing enzymes in the LV-mediated enhancement of 5-FU's antitumor activity, we suppressed the expression of genes related to folic acid metabolism and evaluated the resultant effect on the proliferation inhibitory effect of 5-fluoro-2′-deoxyuridine (FdUrd). Method: We downregulated the expression of thymidylate synthase (TS), folate receptor 1 (FOLR1), methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD), dihydrofolate reductase (DHFR), and phosphoribosylglycinamide formyltransferase (GART) by lipofection of small interfering RNA (siRNA) in DLD-1 and HCT116 cells, and calculated the relative change in IC50 values on 48 hr exposure to FdUrd in comparison with the corresponding IC50 values in control siRNA-treated cells. In cells with TS downregulation, LV-mediated enhancement of sensitivity to FdUrd was also evaluated. Sensitivity to FdUrd was determined using the crystal violet staining method. Results: Treatment with siRNA downregulated the expression of folic acid-metabolizing enzymes. LV enhanced the sensitivity to FdUrd in control siRNA-treated cells in a dose-dependent manner. However, in cells with TS downregulation, LV did not enhance the sensitivity to FdUrd. Downregulation of folic acid-metabolizing enzymes, except TS, decreased the efficacy of FdUrd, although there was little decrease in FdUrd efficacy owing to MTHFR downregulation. Conclusion: The level of TS expression determined the LV requirement, and downregulation of folic acid-metabolizing enzymes, which impaired the folic acid cycle, decreased the efficacy of 5-FU. Comparison of the IC50 values in target siRNA-treated cells and control siRNA-treated cells.DLD-1 cellsHCT116 cellsexpression (%)*IC50 (μM)fold changeexpression (%)*IC50 (μM)fold changeNon-silencing Control siRNA100.000.671.00100.000.251.00TS10.580.010.0114.840.030.12FOLR19.148.6512.9125.122.5910.36MTHFR25.441.432.1348.750.883.52MTHFD9.662.734.0715.061.997.96DHFR8.524.146.1817.231.706.80GART18.905.388.037.102.469.84Values are means (n = 3). *: Expression (%) is the expression at the beginning of FdUrd treatment (at 48 hr after siRNA treatment). Citation Format: Hiroshi Tsukihara, Kenta Tsunekuni, Teiji Takechi. Folic acid-metabolizing enzymes regulate 5-fluorouracil anticancer activity on colorectal cancer cell lines. [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 4659.
Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia
Authors: William G. Wierda, Thomas J. Kipps, Jiri Mayer, Tadeusz Robak, Martin JS Dyer, Richard R. Furman, Peter Hillmen, Stephan Stilgenbauer, Catherine D. Williams, Marek Trneny, Guillaume Cartron, Francisco J. Hernandez-Ilizaliturri, Swaminathan Padmanabhan, Geoffrey W. Chan, Ira V. Gupta, Michele M. Gorczyca, Randy L. Davis, Nedjad Losic, Steen Lisby, Anders Österborg
Journal: Blood (2010)
The expanding role of methotrexate for treating skin disease
Authors: R.J.G. Chalmers
Journal: British Journal of Dermatology (2016)

This month's issue of the Journal contains the British Association of Dermatologists’ updated guidelines for prescribing methotrexate.1 The main focus of the guidelines is directed at psoriasis but a range of other inflammatory dermatoses for which methotrexate is used is also covered. Despite the introduction over the past 30 years of dramatically effective new agents for treating severe psoriasis, methotrexate has retained a pivotal role in this debilitating disease. Because of its very modest costs it is in many parts of the world the only systemic therapy available to a majority of psoriasis sufferers. Furthermore, the range of other skin diseases for which it is now being advocated has been steadily expanding. Sixty‐five years have passed since it was reported that aminopterin, a synthetic analogue of folic acid with antifolate properties, might be beneficial for psoriasis.2 Folate antagonists had been investigated in the 1940s for possible antineoplastic activity in experimental murine sarcoma and then had subsequently been administered to patients with a wide variety of incurable malignant neoplasms. Aminopterin, in particular, appeared to retard progression in patients with both solid and haematological malignancies.3 It was also in the 1940s that corticosteroids first began to be studied. Recognizing that both aminopterin and cortisone appeared to suppress cellular proliferation, the former in neoplastic and the latter in inflammatory diseases such as rheumatoid arthritis, Gubner and colleagues asked themselves the question whether the therapeutic effect of cortisone might be due to ‘a specific hormonal regulatory influence’ or merely to its suppression of ‘connective tissue proliferation’.2 They chose to investigate this in eight patients with severe inflammatory arthritis. They observed a marked reduction in pain and increase in mobility in seven of their eight patients. The dramatic response of long‐standing severe psoriasis in one of them prompted the investigators to administer aminopterin to a further eight patients with psoriasis, all of whom showed marked clearing over 3 weeks. When the closely related but more stable compound methotrexate became available, similar responses in patients with psoriasis were observed. In view of recent interest in the use of methotrexate for atopic eczema, it is noteworthy that they also reported a good response in the single patient with the latter disorder to whom they gave aminopterin. Furthermore, the latter drug is once again receiving attention as a potential treatment for inflammatory diseases including psoriasis.4
Response to comment on “NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis”
Authors: Hui Wang, Montserrat Rojo de la Vega, Donna D. Zhang, Shicang Yu, Hongting Zheng
Journal: Science Translational Medicine (2016)

Multiple factors may affect the outcome of diabetic patients with cancer treated with antioxidant antidiabetic agents.
Abstract LB-251: Radiotherapy sensitizes pancreatic cancer to immunotherapy by promoting T cell infiltration
Authors: Wenxin Zheng, Kinga B. Skowron, Jukes P. Namm, Byron Burnette, Christian Fernandez, Ainhoa Arina, Hua Liang, Michael T. Spiotto, Mitchell C. Posner, Yang-Xin Fu, Ralph R. Weichselbaum
Journal: Cancer Research (2016)

Abstract Pancreatic cancer patients often fail to respond to immunotherapy, such as vaccines or checkpoint inhibitors. It is unknown if an immune phenotype predicts the efficacy of immunotherapy for pancreatic cancer and what standard modalities are required to facilitate the response of pancreatic cancer to immunotherapy. We examined prognostic markers of immune cell infiltration in pancreatic cancer. Pancreatic cancer patients with low CD8+ T cell infiltration and high PD-L1 expression (CD8+ TloPD-L1hi) experienced worse outcomes compared to patients whose tumors demonstrate CD8+ TloPD-L1lo, CD8+ ThiPD-L1hi or CD8+ ThiPD-L1lo profiles. To understand how to improve tumor control in CD8+ TloPD-L1hi pancreatic cancers, we developed a mouse tumor fragment model with a trackable model antigen (SIYRYYGL or SIY) to mimic CD8+ TloPD-L1hi pancreatic cancers. Similar to pancreatic cancers, tumors arising from fragments contained few T cells, even after vaccination. Fragment tumors responded poorly to PD-L1 blockade, SIY vaccination or radiation as individual treatments. By contrast, local ionizing radiation coupled with vaccination increased CD8+ T cell infiltration that was associated with upregulation of CXCL10 and CCL5 chemokines in the tumor, but demonstrated modest inhibition of tumor growth. The addition of an anti-PD-L1 antibody enhanced the effector function of tumor-infiltrating T cells, leading to significantly improved tumor regression and increased survival compared to vaccination and radiation. These results indicate that combination of radiation, vaccination and checkpoint blockade could convert non-T cell-inflamed cancers to T cell-inflamed cancers, and thus effectively treat established pancreatic tumors with an initial CD8+ TloPD-L1hi phenotype. This suggests a novel immunostimulatory role for radiotherapy in the treatment of pancreatic cancer. Citation Format: Wenxin Zheng, Kinga B. Skowron, Jukes P. Namm, Byron Burnette, Christian Fernandez, Ainhoa Arina, Hua Liang, Michael T. Spiotto, Mitchell C. Posner, Yang-Xin Fu, Ralph R. Weichselbaum. Radiotherapy sensitizes pancreatic cancer to immunotherapy by promoting T cell infiltration. [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 LB-251.
Abstract 2801: Arginylation as a novel regulator of prostate cancer progression
Authors: Michael Birnbaum, Akhilesh Kumar, Fangliang Zhang
Journal: Cancer Research (2016)

Abstract Post-translational arginylation, mediated by Arginyltransferase (Ate1), is an important protein modification involved in stress response yet remains poorly studied. Our lab recently reported that a loss of Ate1 is sufficient to induce tumorigenesis and loss of contact inhibition in fibroblasts. However, the role of Ate1 in cancer initiation and progression is not clear. This study examines the effects of Ate1 loss in prostate cancer models of tumorigenesis and progression. We first show that Ate1 is required for normal cellular responses to several types of stress present in cancer. Preliminary data in fibroblasts shows that Ate1 is essential for cell death following oxidative stress, hypoxia, UV and gamma radiation, and apoptosis-inducing drugs. These results inspired further tests to examine if cancer progression may be directly stimulated by a loss of Ate1 through increased cell survival and invasiveness. To study the effects of lost Ate1, we characterize established prostate cancer cell lines with Ate1 stably knocked down. In PC-3 prostate cancer cells, a reduction of Ate1 corresponded with increased invasiveness in the Boyden Chamber invasion assay, and reduced H2O2-induced cell death. In LnCaP prostate cancer cells, reduced Ate1 induced significantly higher anchorage-independent growth during a soft-agar growth assay. In conclusion, our data suggests that the loss of Ate1 in prostate cancer serves to stimulate cancer progression, and that Ate1 protein expression levels may predict malignancy. Citation Format: Michael Birnbaum, Akhilesh Kumar, Fangliang Zhang. Arginylation as a novel regulator of prostate cancer progression. [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 2801.
포스터 전시 : 알코올대사 관련효소 및 cytokine의 유전자 다형성과 알코올성 간경변의 연관성
Authors: 이진우, 이돈행, 이정일, 정석, 김범수, 김형길, 김영수, 권계숙, 신용운, 김명식
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 알코올에 의한 간독성은 개인적 차이가 심하여 과음주자의 약 10-20%에서 알코올성 간경변이 발생한다. 이러한 원인이 잘 알려져 있지 않으나 알코올대사효소나 사이토카인의 유전적 차이 즉, 유전자의 다형성에 의한 가능성이 제시되고 있으며, 이는 결국 알코올성 질환에 개인의 감수성으로 나타날 것으로 생각된다. 이에 연자등은 알코올 탈수소효소(ADH), 알데하이드 탈수소효소(ALDH), cytochrome P450 2E1(CYP2E1)효소와 4가지 사이토카인(IL-1, IL-6, IL-8, TNF-α)의 유전적 다형성과 알코올성 간질환의 연관성을 알아보고자 하였다. 대상과 방법: 정상 성인 36명의 건강대조군과 알코올성 간경변 환자 22명에서 말초 혈액 백혈구에서 DNA를 추출한 후, ADH2, ADH3, ALDH2, CYP2E1, IL-1, IL-6, IL-8, TNF-α 유전자에 대해 PCR을 시행한 후 제한효소들로 처리하여 제한분절길이 다형성으로 유전자형을 나누어 각 유전자형의 출현빈도를 비교하였다. 결과: 1) CYP2E1*c1과 ADH2*1의 경우 각 유전자형의 출현빈도가 건강대조군에 비하여 알코올성 간경변군에서 유의하게 높았다(CYP2E1*c1; 간경변군:건강대조군=0.864:0.667, p=0.019/ ADH2*1; 간경변군:건강대조군＝0.727:0.500, p=0.043). 2) 경계역상 유의성을 가진 비교결과로는 ALDH2*2의 경우 알코올성 간경변군과 대조군의 비교시 대조군에서 높은 경향을 보였다(알코올질환군: 대조군=0.114:0.264, p=0.053). 3) 상기 두군에서 IL-1, IL-6, IL-8, TNF-燒?유전자 형의 출현빈도는 유의한 차이가 없었다. 결론: 이상의 결과로 CYP2E1*c1과 ADH2*1의 유전자형을 가진 사람은 알코올성 간질환에 대한 감수성이 높을 것으로 생각되며, 염증성 사이토카인의 유전적 다형성과 알코올성 간경변의 연관성은 관찰할 수 없었다.
Abstract P415: Association of Baseline Physical Activity by Pedometer Counts and Nutritional Behavior on Metabolic Syndrome in the NAVIGATOR Study
Authors: Kim Huffman, Jie-Lena Sun, Laine Thomas, Connie Bales, Robert Califf, Jaako Tuomilehto, Thomas Yates, Melanie Davies, Rury Holman, John McMurray, Angelyn Bethel, Steven Haffner, William Kraus
Journal: Circulation (2013)

Metabolic syndrome (MS) is the cardiometabolic risk cluster comprised of elevated fasting glucose, hypertension, elevated triglycerides, reduced HDL-cholesterol and enlarged waist circumference. Wh...
Abstract 905: Pterostilbene (PTER) suppresses breast cancer brain metastasis by targeting a c-Met mediated inflammation network
Authors: Fei Xing, Yin Liu, Sambad Sharma, Kerui Wu, Kounosuke Watabe
Journal: Cancer Research (2016)

Abstract At the late stage of breast cancer, most patients develop metastatic lesions and the brain is one of the major metastatic sites. Brain metastasis profoundly affects the cognitive and sensory function as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. The result of our newly developed gene set enrichment analysis (GSEA)-based pathway screening indicates that c-Met pathway is highly activated among the patients who developed early brain metastasis. To identify a novel target of c-Met pathway in brain metastasis, we performed the microarray analysis in two brain metastatic cell lines with the expression of doxycycline-inducible sh-cMet. Our results indicate that a group of inflammatory cytokines including IL1b, IL8 and CXCL1 were significantly induced by c-Met activation. Furthermore, we found that IL1b was able to induce the secretion of HGF (hepatocyte growth factor) from tumor associated astrocytes (TAA) which in turn activates c-Met pathway in cancer cells. Our results of endothelial cell tube formation assays also strongly suggest that cMet-induced IL8 and the activation of its receptor, CXCL1, promote tumor angiogenesis which is essential for the metastatic growth of cancer cells. Natural compounds (NC) have been extensively studied for their anti-tumor effects. However, much less studies have been done on NC for the treatment/prevention of brain tumors mainly due to the obstacle of Blood-brain-barrier (BBB) permeability. To identify the NCs that can be used for treating brain metastasis, we performed pathway analysis which only focused on BBB-permeable NC. The results of GSEA indicate that Resveratrol-targeting genes were significantly enriched among those patients who developed brain metastasis compared to metastasis-free patients. Furthermore, we found that the one of derivatives of Resveratrol, Pterostilbene (PTER), showed significantly more potent activity than Resveratrol and suppressed brain metastasis in vitro and in vivo by targeting the c-Met oncogene. These findings suggest that TAA-mediated c-Met activation plays a key role in brain metastasis and that PTER is a potential therapeutic agent to treat brain metastasis by suppressing the c-Met expression. Citation Format: Fei Xing, Yin Liu, Sambad Sharma, Kerui Wu, Kounosuke Watabe. Pterostilbene (PTER) suppresses breast cancer brain metastasis by targeting a c-Met mediated inflammation network. [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 905.