tbuckley/cabot-search huggingface dataset:
External validation of preoperative nomograms for predicting pathological stage of prostate cancer: Analysis of 716 Japanese cases
Authors: K. Kanao, T. Shinojima, J. Nakashima, T. Ohigashi, E. Kikuchi, A. Miyajima, K. Nakagawa, M. Oya
Journal: Journal of Clinical Oncology (2009)

e16078 Background: For the purpose of predicting pathological stage of prostate cancer, Partin et al have developed preoperative nomograms (Partin Tables). Partin tables were modified and updated twice to reflect a more contemporary condition of prostate cancer stage at diagnosis. Recently similar Tables using 1188 Japanese patients were also developed. Although the characteristics of prostate cancer are thought to vary between Asian and Western patients, there are few studies to validate the prognostic accuracy of Partin tables in Asian patients and there is no study to validate three Partin table simultaneously. In this study we evaluate the validity of thee Partin Tables and Japanese Tables for our 716 of Japanese cases. Methods: Seven hundred sixteen patients were analyzed retrospectively who underwent radical prostatectomy in our institute without neoadjvant endocrine therapy. In four Tables (Partin 97, 01, 07 and Japanese Tables) the patient's distributions were evaluated and the fitness for each models were also evaluated using AIC (Akaike's information criteria). The probabilities of organ confined disease for each case were calculated from four nomograms and external validation was performed using ROC analysis and calibration. Results: Preoperative clinical stage of our cases were 587 with T1c, 140 with T2a, 20 with T2b and 63 with T2c. PSA at diagnosis was 10.45±0.60 (mean±SE). AIC of each Tables was 975.0 in 97 Tables, 974.3 in 01 Tables, 975.4 in 07 Tables and 973.6 in Japanese Tables. The area under the ROC curve (AUC)of each Tables was 0.619 in 97 Tables, 0.623 in 01 Tables, 0.614 in 07 Tables and 0.614 in Japanese Tables. There were no difference of calibration plots in four Tables and in general actual probabilities of organ confined were lower than predicted probability. Conclusions: This study showed that four nomograms have no difference in discrimination and prediction ability to our cases, but when we use these nomograms it is necessary to estimate the probability to be low than predicted probability. No significant financial relationships to disclose.
Abstract 3952: BRE: a genetic interactor of BRCA2
Authors: Kajal Biswas, Suhwan Chang, Subha Philip, Shyam K. Sharan
Journal: Cancer Research (2015)

Abstract Mutations in breast cancer susceptibility genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Though BRCA associated tumor tissues showed inactivation of both alleles, in primary cells mutations in both copies affect cell viability. This suggests that BRCA1 or 2 loss mediated tumorigenesis process needs other factors. In this study, MSCV (Murine Stem Cell Virus) retroviral mediated insertional mutagenesis approach was used in conditional Brca2 mutant mES (mouse embryonic stem) cells to identify and characterize genetic interactors of BRCA2. One of the factors identified in this screen is brain and reproductive organ expressed protein BRE. BRE is an anti-apoptotic protein and also a component of the BRCA1-A complex that specifically recognizes ‘Lys-63′-linked ubiquitinated histones H2A and H2AX at DNA lesions sites. Overexpression of BRE results into perturbation of DNA damage induced G1/S cell cycle checkpoint by preventing DNA damage induced degradation of CDC25a phosphatase. Further it was found that the stabilization of CDC25a phosphatase in BRE overexpressing cells on DNA damage is mediated via ubiquitin-specific-processing protease 7 (USP7). We are now examining the expression of BRE and CDC25a in BRCA2 deficient tumors. Citation Format: Kajal Biswas, Suhwan Chang, Subha Philip, Shyam K. Sharan. BRE: a genetic interactor of BRCA2. [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 3952. doi:10.1158/1538-7445.AM2015-3952
Abstract IA22: Reprograming the tumor microenvironment to facilitate responses to immunotherapy
Authors: David Glenn DeNardo
Journal: Cancer Research (2016)

Abstract Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy. The results of these pre-clinical studies have led to the development of a new clinical trial (NCT02546531) testing the combination of FAK inhibition (Defactinib) with Pembrolizumab and Gemcitabine in advanced PDAC Patients. Citation Format: David Glenn DeNardo.{Authors}. Reprograming the tumor microenvironment to facilitate responses to immunotherapy. [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 IA22.
Abstract 4949: HAS2 is a critical effector for AGL mediated regulation of tumor growth
Authors: Sunny Guin, Yuanbin Ru, Carolyn R. Lew, Neeraj Agarwal, Charles Owens, Dan Theodorescu
Journal: Cancer Research (2015)

Abstract In bladder cancer, reduced levels of Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL), an enzyme involved in glycogenolysis and mutated in glycogen storage disease type III, enhances proliferation in vitro and tumor growth in vivo. To identify how reduced levels of AGL promote bladder cancer growth, we gene expression profiled two bladder cancer cell lines with and without siRNA mediated AGL depletion. This identified that hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis, is upregulated with AGL depletion. We validated this finding in several additional bladder cancer cell lines and also found that HA levels were 2-fold higher bladder cancer cells with low AGL compared to control. Interestingly, siRNA induced knockdown of HAS2 preferentially reduced monolayer, anchorage independent and xenograft growth in bladder cancer cells with low AGL. 4-Methylumbelliferone (4-MU), an inhibitor of HA synthesis, had similar effects. Analysis of human bladder cancer tissues showed that AGL and HAS2 mRNA expression are negatively correlated in 5/8 patient datasets (N = 725). Bladder cancer patients with high HAS2 and low AGL expression had worse survival than patients with the reciprocal relationship between these two genes suggesting that HAS2 is a driver of bladder tumor growth with AGL loss establish the HAS2/HA axis as a major driver and target of therapy in bladder tumors with low AGL. Citation Format: Sunny Guin, Yuanbin Ru, Carolyn R. Lew, Neeraj Agarwal, Charles Owens, Dan Theodorescu. HAS2 is a critical effector for AGL mediated regulation of tumor growth. [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 4949. doi:10.1158/1538-7445.AM2015-4949
Autologous Peripheral Stem Cell Transplantation(ASCT) for Refractory or Recurrent Hodgkin Lymphoma.
Authors: Mitsuru Koike, Masayuki Kato, Yo Kato, Tasuku Saito, Madoka Takimoto, Michiko Irei, Yasuyuki Inoue, Yasushi Shibuya, Junki Koike, Takao Suzuki, Masatomo Takahashi
Journal: Blood (2005)
Bortezomib and High Dose Melphalan (Bor-HDM) Compared to HDM Conditioning for the Treatment of Transplant Eligible Multiple Myeloma: Report from a Single Center
Authors: Victor H Jimenez-Zepeda, Peter Duggan, Paola Neri, Ahsan Chaudhry, Marcia Culham, Joanne Luider, Fariborz Rashid-Kolvear, Nizar J Bahlis
Journal: Blood (2015)
Phase I Trial of Vorinostat (SAHA) in Combination with Alvocidib (Flavopiridol) in Patients with Relapsed, Refractory or (Selected) Poor Prognosis Acute Leukemia or Refractory Anemia with Excess Blasts-2 (RAEB-2)
Authors: Steven Grant, Sarah Kolla, Leonardo Andres Sirulnik, Geoffrey Shapiro, Jeffrey Supko, Brenda Cooper, Edward Perkins, Viswanathan Ramakrishnan, Igor Espinoza-Delgado, M B Tombes, John D Roberts
Journal: Blood (2008)
Pediatric Myelodysplastic Syndrome: Experience from a Single Center
Authors: Mualla Cetin, Sule Unal, Turan Bayhan, Selin Aytac, Baris Kuskonmaz, Betul Tavil, Duygu Uckan-Cetinkaya, Fatma Gumruk, A. Murat Tuncer
Journal: Blood (2014)
Studies with the Nanobody That Detects the Gain-of-Function of von Willebrand Factor in a Cohort of Patients with Type 2B von Willebrand Disease: Correlation with Platelet Count, VWF Multimers and Molecular Defects.
Authors: Augusto B. Federici, Luciano Baronciani, Maria T. Canciani, Barbara Moroni, Carlo Balduini, Pier M. Mannucci, Peter J. Lenting, Philip G. de Groot
Journal: Blood (2006)
Recombinant Factor VIIa (rFVIIa) Is Safe and Effective When Used to Treat Acute Bleeding Episodes and to Prevent Bleeding During Surgery in Patients with Acquired Hemophilia: Updated Assessment From the Hemostasis and Thrombosis Research Society (HTRS) Registry AH Database,
Authors: Alice D. Ma, Craig M. Kessler, Robert Z. Gut, David L. Cooper
Journal: Blood (2011)
Abstract 675: Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia
Authors: Brent M. Kuenzi, Lily L. Remsing Rix, Sateesh S. Kunigal, Fumi Kinose, Claire E. Knezevic, Gabriela Wright, Jodi L. Kroeger, Jeffrey E. Lancet, Eric Padron, Uwe Rix
Journal: Cancer Research (2015)

Abstract GSK3 alpha has been shown to be a new target in the treatment of acute myeloid leukemia (AML); however current GSK3 inhibitors are unselective and target both GSK3 alpha and GSK3 beta. Interestingly, a known pan-GSK3 inhibitor LiCl has been previously investigated for the treatment of AML yet has met limited clinical success. This could be partly due to the fact that pan-GSK3 inhibition results in beta-catenin stabilization, which has been shown to mediate hematopoietic self-renewal and leukemogenesis. As beta-catenin stabilization requires inhibition of both kinases and most GSK3 inhibitors target GSK3 alpha and GSK3 beta with equal potency, these compounds may possess some significant limitations. We have previously shown GSK3 alpha to be a prominent target of the intended MET inhibitor tivantinib (ARQ197) and that tivantinib shows some specificity for GSK3 alpha over GSK3 beta. We thus hypothesized that tivantinib would be an effective therapy for the treatment of AML. Consistently, tivantinib potently inhibited cellular viability across several AML cell lines. Using an unbiased, mass-spectrometry based chemical proteomics approach; we confirmed GSK3 alpha (and to a slightly lesser extent GSK3 beta) to be targeted by tivantinib in AML. Tivantinib strongly induced apoptosis as compared to the pan-GSK3 inhibitor LiCl in these cells while LiCl showed larger effects on cell differentiation. Interestingly tivantinib caused less stabilization of beta-catenin as compared to LiCl. Subsequent drug combination studies identified the Bcl-2 inhibitor ABT-199 to synergize with tivantinib and to amplify apoptosis as seen by PARP1 cleavage. Furthermore, the combination of tivantinib with ABT-199 completely abrogated beta-catenin stabilization. Tivantinib was able to significantly inhibit colony formation of primary AML patient bone marrow mononuclear cells (BMNCs) and ABT-199 combination showed significant benefit over tivantinib or ABT-199 alone. In summary, tivantinib has potent anticancer activity in AML based on targeting GSK3 alpha; and tivantinib single agent or combination with ABT-199 may represent a novel and exciting opportunity for the treatment of AML. Citation Format: Brent M. Kuenzi, Lily L. Remsing Rix, Sateesh S. Kunigal, Fumi Kinose, Claire E. Knezevic, Gabriela Wright, Jodi L. Kroeger, Jeffrey E. Lancet, Eric Padron, Uwe Rix. Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia. [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 675. doi:10.1158/1538-7445.AM2015-675
Abstract 1823: A novel web interface to facilitate pathology directed mass spectrometry
Authors: Erin H. Seeley, R. Ryan Dunkerley, Andre L. Moreira, Robert J. Downey, Greg W. Kilby
Journal: Cancer Research (2015)

Abstract Clinical proteomics studies often involve multiple investigators located at different physical locations necessitating a centralized platform for joint access to data and other information pertinent to the study. To help communicate pathology targets of interests from remote researchers to the on-site technical team, the Pathology Directed Mass Spectrometry (PDMS) web application was developed. PDMS was designed to be a secure, online digital pathology platform specifically configured for down-stream mass spectrometry imaging (MSI) analysis. Hosting ultra-high resolution digital microscopy images of stained serial tissue sections, PDMS allows researchers to zoom into their samples to review and annotate specific areas for analysis. Once finalized, annotated images are exported from PDMS for MSI targeting. Built for HTML5 browsers, PDMS was deployed in a secure LAMP (Linux, Apache, MySQL, PHP) environment, utilizing a Javascript visualization engine and server-side conversion tools. In a pathology directed mass spectrometry profiling experiment, two sections of a tissue specimen are collected, one on a mass spectrometry target and one that is stained for histological evaluation. A pathologist annotates a digital microscopy image to indicate areas of interest for mass spectral analysis. The annotated image is then merged with an image of the unstained section and after appropriate sample preparation, mass spectra are collected from the annotated areas. A major advantage to this type of analysis is that it is high throughput and is conducive to downstream biostatistical analysis for biomarker discovery. The PDMS software has been successfully used in the molecular differentiation of histological patterns in stage I pulmonary carcinomas as part of a joint collaboration with Memorial Sloan Kettering Cancer Center. Image annotation was carried out remotely prior to mass spectral analysis in house. Statistical analyses of the mass spectral data resulted in over 85% classification accuracies in differentiating histological tumor subtypes within individual pulmonary carcinoma patient samples. Citation Format: Erin H. Seeley, R. Ryan Dunkerley, Andre L. Moreira, Robert J. Downey, Greg W. Kilby. A novel web interface to facilitate pathology directed mass spectrometry. [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 1823. doi:10.1158/1538-7445.AM2015-1823
Abstract 4714: Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases
Authors: Brooke M. Emerling, Zhiwei Yang, Ryan Loughran, T.Jonathan Yang, Jared Johnson, Rajan Pragani, Mindy Davis, Min Shen, Matthew Boxer, Anton Simeonov, Lewis C. Cantley
Journal: Cancer Research (2015)

Abstract The bulk of cellular phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) is generated by the canonical pathway in which a 5-kinase converts phosphatidylinositol-4-phosphate (PI-4-P) to PI-4,5-P2. However, several years ago we discovered that PI-4, 5-P2 can also be generated at intracellular sites by a family of kinases that phosphorylate the 4 position of phosphatidylinositol-5-phosphate (PI-5-P), a lipid that was not previously known to exist in nature. These enzymes are called the type 2 phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks). To date, we have shown that a subset of breast cancers express high levels of PI5P4Kα and/or β, and have provided evidence that these kinases are essential for growth in the absence of p53 (Emerling et al., 2013). Furthermore, we showed that PI5P4Kα and β play critical roles in mediating changes in metabolism in response to cellular stress, in particular, stress that occurs in the absence of p53. Here, we disclose the discovery of potent and selective inhibitors of PI5P4K (Kis in the range of 10 to 200 nM). These novel PI5P4K inhibitors have provided us with powerful tools to further investigate the role of the PI5P4K enzymes in cancer metabolism. Through pharmacological inhibition of PI5P4K, we now have support that PI5P4K provides an alternative pathway to p53 in regard to mediating responses to metabolic and oxidative stress, thereby suggesting that the PI5P4K enzymes are essential for survival mechanisms when p53 function is lost. Above all, these inhibitors may be effective therapies not only for breast cancers with genetic aberrations in TP53, but in all cancer types with loss of p53 function. Supported by DOD Breast Research Program Breakthrough Award to B.M.E. References Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Wulf G, Bell EL, Shim H, Choo-Wing R, Bellinger G, Lamia KA, Rameh LE, Sasaki A, Asara JM, Yuan X, Bullock A, Brown V, Signoretti S, and Cantley LC. (2013) Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53 Null Tumors. Cell. Nov 7; 155 (4): 844-57. Citation Format: Brooke M. Emerling, Zhiwei Yang, Ryan Loughran, T.Jonathan Yang, Jared Johnson, Rajan Pragani, Mindy Davis, Min Shen, Matthew Boxer, Anton Simeonov, Lewis C. Cantley. Targeting p53 mutant cancers through inhibition of the phosphatidylinositol-5-phosphate 4-kinases. [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 4714. doi:10.1158/1538-7445.AM2015-4714
Establishment and Drug Sensitivity, Gene Expression and Epigenetic Characterization of a Pediatric Leukemia Cell Line (POETIC1) with Primary Resistance to Decitabine
Authors: Maneka Perinpanayagam, Anna Kovalchuk, Yibing Ruan, Sungmyung Kang, Aarthi Jayanthan, Olga Kovalchuk, Jessica Boklan, Aru Narendran
Journal: Blood (2014)
Abstract 883: Body mass, smoking habit, and hypertension and renal cell cancer survival
Authors: Jung Eun Lee, Nayeon Kim, Hans-Olov Adami, Per Lindblad
Journal: Cancer Research (2015)

Abstract Background: A recent meta-analysis showed higher survival rate among over-weight and obese renal cell cancer (RCC) patients. Given that obesity, smoking and hypertension are well-established risk factors for RCC development, it is therefore important to know whether these factors are associated with RCC prognosis. Objectives: We evaluated the associations of body mass index (BMI), smoking and hypertension with RCC survival in a population-based cohort of incident RCC cases assembled from a Swedish case-control study. Methods: We analyzed a total of 371 RCC cases diagnosed in 1988-1992 with follow-up through Dec 31, 2011. Information on weight, height, smoking habit and hypertension was obtained through face-to-face interviews. Mortality information was determined through linkage to the National Cancer Registry; 298 deaths were identified, with 148 of those having RCC as the underlying cause of death, during an average of 9.9 years of follow-up. We calculated hazard ratios (HR)s and 95% confidence interval (CI)s using the Cox proportional hazards models. Results: We confirmed that lifetime smoking and BMI at highest adult weight were associated with a worse overall survival among RCC patients. When we examined RCC-specific survival, the associations were not statistically significant; multivariate HR (95% CI) was 0.89 (0.54-1.49) for 20 or greater pack-years of smoking compared to never smokers. For BMI at highest adult weight, multivariate HR (95% CI) was 0.99 (0.53-1.87) comparing 35 or greater levels of BMI with less than 27 kg/m2 of BMI. History of hypertension was not associated with overall or RCC-specific survival. Conclusions: We found a decreasing trend of overall survival with increasing prediagnostic BMI and lifetime smoking, but no significant associations of these factors and hypertension with RCC-specific survival among RCC patients. Citation Format: Jung Eun Lee, Nayeon Kim, Hans-Olov Adami, Per Lindblad. Body mass, smoking habit, and hypertension and renal cell cancer survival. [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 883. doi:10.1158/1538-7445.AM2015-883
Method of Mobilization: Implication on Cell Subsets in the Graft and Immune Reconstitution Post Autologous Hematopoietic Cell Transplantation (AHCT)
Authors: Melhem M. Solh, Rathmann Kristin, Sauvi chang-Fong, Jeremiah Oyer, Wesam B. Ahmed, Alicja J Copik, Yasser Khaled
Journal: Blood (2014)