tbuckley/cabot-search huggingface dataset:
High Density SNP Array Analysis of Acute Promyelocytic Leukemia (APL) Detects New Common Genomic Copy Number Alterations as Possible Cooperating Lesions
Authors: Daniel Nowak, Marion Klaumuenzer, Benjamin Hanfstein, Maximilian Mossner, Florian Nolte, Verena Nowak, Julia Oblaender, Seishi Ogawa, Alexander Kohlmann, Wolfgang Seifarth, Alice Fabarius, Philipp Erben, Susanne Saussele, Martin C Mueller, Eva Lengfelder, Wolf Karsten Hofmann
Journal: Blood (2010)
CXCR5 Polymorphisms in Non-Hodgkin Lymphoma (NHL) Risk and Prognosis.
Authors: Bridget Charbonneau, Alice H Wang, Anne J. Novak, Stephen M. Ansell, Andrew L. Feldman, Yan W Asmann, Julie M Cunningham, Matthew J Maurer, Ahmet Dogan, Thomas M Habermann, Brian K Link, Susan L Slager, James R Cerhan
Journal: Blood (2012)
Abstract 1942: Regulation of GRNMB transcription and cellular effects by chondroitin 4-sulfation
Authors: Joanne Kramer Tobacman, Leo Feferman, Sumit Bhattacharyya
Journal: Cancer Research (2015)

Abstract Increased expression of glycoprotein (transmembrane) NMB (GPNMB; osteoactivin) has been identified in triple negative breast cancer, melanoma, glioma, and hepatocellular carcinoma, and followed decline in expression of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase). The expression and regulation of GPNMB was evaluated in HepG2 cells and in ARSB-deficient and control C57BL/6J mouse hepatic tissue. Increased expression of GPNMB was attributable to promoter activation by phospho(Ser)MITF (microphthalmia-associated transcription factor), the phosphorylation of which was activated by phospho(Ser)-p38 MAPK. When ARSB was reduced, nuclear phospho-MITF increased and GPNMB promoter activity increased, as detected by Renilla reniformis luciferase assay. Chromatin immunoprecipitation assay confirmed that phospho-MITF bound to a specific motif in the GPNMB promoter, and binding increased when ARSB was silenced. Up-regulation of promoter activity increased the expression of GPNMB message and the synthesis of GPNMB protein in the HepG2 cells and ARSB-null mouse liver. The tyrosine phosphatase SHP2 bound more tightly to C4S when ARSB was reduced, leading to inhibition of SHP2 activity and reduced removal of phosphate from Tyr182 of phospho-p38 MAPK. The increase in C4S stimulated phospho(Ser)-p38 MAPK by activation of RhoA, leading to MITF phosphorylation and increased GPNMB expression. Silencing GPNMB by siRNA reduced phosphorylation of ERK and expression of matrix metalloproteinase (MMP)-9, consistent with effects on hepatic cell invasiveness. These findings indicate that ARSB-induced changes in chondroitin 4-sulfation impact on critical phosphorylations mediated by SHP2 and p38 MAPK, leading to activation of MITF and increased expression of GPNMB. The interaction between chondroitin 4-sulfation and phosphorylations may regulate vital cell processes, including transcriptional events and cell-matrix interactions. Citation Format: Joanne Kramer Tobacman, Leo Feferman, Sumit Bhattacharyya. Regulation of GRNMB transcription and cellular effects by chondroitin 4-sulfation. [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 1942. doi:10.1158/1538-7445.AM2015-1942
Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma
Authors: David A Reardon, Andrew B Lassman, Martin van den Bent, Priya Kumthekar, Ryan Merrell, Andrew M Scott, Lisa Fichtel, Erik P Sulman, Erica Gomez, JuDee Fischer, Ho-Jin Lee, Wijith Munasinghe, Hao Xiong, Helen Mandich, Lisa Roberts-Rapp, Peter Ansell, Kyle D Holen, Hui K Gan
Journal: Neuro-Oncology (2016)

The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR).
Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis
Authors: Kasper S. Wang, Greg Tiao, Lee M. Bass, Paula M. Hertel, Douglas Mogul, Nanda Kerkar, Matthew Clifton, Colleen Azen, Laura Bull, Philip Rosenthal, Dylan Stewart, Riccardo Superina, Ronen Arnon, Molly Bozic, Mary L. Brandt, Patrick A. Dillon, Annie Fecteau, Kishore Iyer, Binita Kamath, Saul Karpen, Frederick Karrer, Kathleen M. Loomes, Cara Mack, Peter Mattei, Alexander Miethke, Kyle Soltys, Yumirle P. Turmelle, Karen West, Jessica Zagory, Cat Goodhue, Benjamin L. Shneider
Journal: Hepatology (2016)

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis‐1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ‐glutamyl transpeptidase disease (levels &lt;100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder‐to‐colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. &gt;24 months postoperatively, respectively; P &lt; 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. Conclusion : This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (H epatology 2017;65:1645‐1654).
Abstract 1509: Leptin drives mammary stem cell self-renewal via the mTOR pathway
Authors: Ray Esper, Michael Dame, Shannon McClintock, Becky Simon, Max Wicha, Dean Brenner
Journal: Cancer Research (2015)

Abstract Normal tissue stem cells exist in either a quiescent or proliferating/self-renewing phenotypic state with different patterns of gene expression. In the breast, the CD44+/CD24− cells are retained in a quiescent state, while the ALDH+ stem cells are actively self-renewing cells; the quiescent CD44+/CD24− cells must transition through a self-renewing ALDH+ state in order to differentiate into mature mammary cells. The adipose-rich stroma that makes up the stem cell niche in the human breast is a source of leptin that may alter stem cell phenotype in a paracrine manner. A larger population of proliferating breast stem cells could, in turn, increase the risk of breast cancer. We previously demonstrated that the increased local leptin/adiponectin ratio that commonly occurs in breast tissue of obese women promotes increased breast stem cell self-renewal leading to a larger population of stem cells in vivo, and that the mTOR pathway is activated in normal human mammary stem cells by physiologic concentrations of adipokines, including leptin. There was a physiologic dose response, with a measurable increase in mTOR activity over baseline with 31.25 ng/ml leptin, and a near maximal effect with 125 ng/ml. Here, we isolated the quiescent and proliferating stem cell fractions from human reduction mammoplasty samples and measured basal mTOR activity by ELISA for phosphorylated S6 ribosomal protein (pS6/tS6 ratio), which was greater in the proliferating ALDH+ cells. The quiescent stem cell fraction was treated with physiologic concentrations of leptin prior to resorting with FACS to measure a transition from a CD44+/CD24− to an ALDH+ proliferating phenotype. Parallel quiescent stem cells treated with the mTOR inhibitor everolimus simultaneously with leptin demonstrated that mTOR activity is necessary for this phenotypic switch. If inflammatory adipokines promote stem cell symmetric self-renewal by activating mTOR, targeted interventions may maintain potential tumor-initiating cells in a quiescent state and reduce cancer incidence. Citation Format: Ray Esper, Michael Dame, Shannon McClintock, Becky Simon, Max Wicha, Dean Brenner. Leptin drives mammary stem cell self-renewal via the mTOR pathway. [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 1509. doi:10.1158/1538-7445.AM2015-1509
Applicability of the World Health Organization recommended new shorter regimen in a multidrug-resistant tuberculosis high burden country
Authors: Arshad Javaid, Nafees Ahmad, Amer Hayat Khan, Zubair Shaheen
Journal: European Respiratory Journal (2016)

In order to improve the adherence and treatment outcomes of multidrug-resistant (MDR) tuberculosis (TB) patients, the World Health Organization (WHO) has recently recommended a new, shorter and cheaper treatment regimen. The new regimen, comprised of 4–6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, ethambutol and high dose isoniazid followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol [1], has produced excellent outcomes under operational research conditions is various settings [2–4]. However, the recommendation that it should be used only for MDR-TB patients who are neither previously treated with second-line anti-TB drugs, nor resistant to fluoroquinolones or injectable second-line anti-TB drugs [1], generates concerns about its applicability in MDR-TB high burden countries [5]. In the current cross-sectional study, culture-confirmed MDR-TB patients treated at two units for programmatic management of drug-resistant TB in Pakistan were evaluated for drug resistance pattern and eligibility to be treated with the new shorter regimen. High prevalence of ofloxacin resistance should not limit the applicability of the new shorter regimen in Pakistan <http://ow.ly/HCAs306dUjU> The authors acknowledge the record keeping staff at the study sites for their help in conducting this study, and have no financial support to report and declare no conflict of interest. Author contributions: N. Ahmad, A. Javaid, Z. Shaheen and A.H. Khan designed the study. N. Ahmad, A. Javaid and Z. Shaheen collected the data. N. Ahmad analysed the data and wrote the manuscript. A. Javaid, Z. Shaheen and A.H. Khan critically reviewed the manuscript.
The Sil Index Is a Useful Prognostic Indicator for Diffuse Large B-Cell Lymphoma
Authors: Naoto Tomita, Taisei Suzuki, Kazuho Miyashita, Wataru Yamamoto, Kenji Motohashi, Takayoshi Tachibana, Hirotaka Takasaki, Rika Kawasaki, Maki Hagihara, Chizuko Hashimoto, Sachiya Takemura, Hideyuki Koharazawa, Etsuko Yamazaki, Jun Taguchi, Katsumichi Fujimaki, Hiroyuki Fujita, Rika Sakai, Shin Fujisawa, Shigeki Motomura, Keisuke Kawamoto, Hirohito Sone, Jun Takizawa
Journal: Blood (2015)
Abstract 1816: Impact of 5FU and radiation on replication of interferon-expressing adenovirus
Authors: Jordan Sell
Journal: Cancer Research (2015)

Abstract Pancreatic Cancer is a disease for which there are very limited efficacious treatments, resulting in a 5-year survival rate for affected patients around only 6%. A recombinant oncolytic adenovirus (OAd-IFN) developed by our group to target pancreatic cancer utilizes enhanced oncolysis with an overexpression of the adenoviral death protein, enhanced infectivity with a genetically modified fiber, conditional replication targeted to pancreatic cancer using the Cox-2 promoter, and an expression of human interferonαto enhance the therapeutic effects of chemotherapy and radiation through the antitumor effects of the cytokine. Our previous work analyzing the therapeutic abilities of IFN expressing vectors in human pancreatic cancer xenografts in immonudeficient nude mice and in syngeneic hamster pancreatic cancer nodules in immunocompetent Syrian hamsters, showed a more evident antitumor effect of OAd-IFN in the latter models. This suggests the success of OAd-IFN as an immune system stimulator, making it a promising candidate for combination therapy approaches. The goal of this study is to investigate the possibility for use of OAd-IFN as a therapy for pancreatic cancer in conjunction with 5FU and radiation. Specifically, the adenoviral replicative ability was measured within pancreatic cancer Mia-Paca 2 cells under various conditions of 5FU and radiation exposure. Replication was analyzed by a correlation to the increase in amount of viral DNA extracted from treated cells at two time points post infection. In two preliminary trials, cells were infected with the virus two days prior to receiving 5FU and radiation, and another group of cells was treated with 5FU before viral infection. Based on the initial data collected, radiation seemed to have no effect on viral replication. 5FU treatment prior to viral infection resulted in an increase in replication at low dose, and a decrease in replication with high dose, however, this effect was only seen at the first time point 3 days after infection. Similarly, 5FU treatment post infection showed a minor dose dependent inhibition of viral replication at high doses, with little to no effect observed in the low dose. Combining viral infection with 5FU appears to have an impact on the replication of OAd-IFN in vitro; however, further trials need to be done to explore the effect of various timing among viral infection and therapy treatments as well as different therapy concentrations and viral titers to further analyze the potential combination therapies. Citation Format: Jordan Sell. Impact of 5FU and radiation on replication of interferon-expressing adenovirus. [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 1816. doi:10.1158/1538-7445.AM2015-1816
Abstract 2463: Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights
Authors: Puja Sapra, Boris Shor, Maureen Dougher, Jennifer Kahler, Michelle Mack, Jane Xu, Shuyan Lu, Eugene Melamud, Fang Wang, Edward Rosfjord
Journal: Cancer Research (2015)

Abstract Targeted treatment with antibody-drug conjugates (ADCs) can lead to dramatic regressions of solid tumors; combination therapies with the ADCs that could potentially help achieve long-term disease control remain largely unexplored. The aim of the study is to investigate most promising combination regimens of auristatin-based conjugates in preclinical models of cancer. A tool ADC, an auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and permeable auristatin analogs were combined with dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of common cancer cell lines of breast, lung or ovarian origin. Drug combinations were tested for their effects in vitro on cell viability, apoptosis, cell cycle or modulation of PI3K/mTOR pathway markers. Anti-tumor efficacy of selected combinations was also evaluated in a 5T4-positive human breast or lung tumor xenografts in vivo. Remarkably, ADC and auristatin analogs resulted in synergistic or additive effects on cell cytotoxicity when combined with PF-384 or with taxanes in vitro. ADC/PF-384, auristatin/PF-384 and ADC/Paclitaxel (PTX), auristatin/PTX combinations showed enhanced induction of apoptosis and selective attenuation of the downstream phospho-markers of the PI3K/mTOR pathway. Quantitative proteomic analysis of cells treated with auristatin-based agents and PF-384 alone or in combination revealed novel and unique effects on key components of mRNA translation, including translation initiation or elongation factors. In human lung or breast cancer xenograft models, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/PTX produced substantially greater antitumor effects with longer average survival as compared to monotherapy treatments. Our results provide strong rationale for combining 5T4-ADC with PI3K/mTOR pathway inhibitors or taxanes. New biological insights into molecular mechanisms underlying synergistic effects of ADC - drug combinations suggest/reveal that synergies are mediated by payload's mode of action. These findings can be applicable to several ADCs employing microtubule inhibitors that are undergoing clinical evaluation. Citation Format: Puja Sapra, Boris Shor, Maureen Dougher, Jennifer Kahler, Michelle Mack, Jane Xu, Shuyan Lu, Eugene Melamud, Fang Wang, Edward Rosfjord. Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights. [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 2463. doi:10.1158/1538-7445.AM2015-2463
Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial
Authors: Vincent Chung, Aaron S. Mansfield, Fadi Braiteh, Donald Richards, Henry Durivage, Richard S. Ungerleider, Francis Johnson, John S. Kovach
Journal: Clinical Cancer Research (2016)

Abstract Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.
Rotorの検出において”ExTRaマッピング”と呼ばれる新しく開発された(準)リアルタイムフェーズマッピングシステムはNavX Activationマッピングより優れている
Authors: Fukui Akira, Yamaguchi Takanori, Nagamoto Yasutsugu, Inada Shin, Nakazawa Kazuo, Ashihara Takashi, Tsuchiya Takeshi
Journal: Circulation (2015)
Effect of Chemotherapy on the Distress and Quality of Life of Cancer Patients.
Authors: Mirsa B. Hussain, Gangadharan P. Sarita, Nandakumar Devi, Bejoy C. Thomas, Krishnan Rita, Kunnambath Ramdas, Balakrishna Rajan, Manoj Pandey, Geetha N. Narayanan
Journal: Blood (2004)
Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult patients with cancer with advanced solid tumors.
Authors: A. Thomas-Schoemann, M. Tod, O. Mir, N. Bancelin, R. Coriat, F. Taieb, P. Boudou-Rouquette, H. Abbas, S. Ropert, J. Durand, A. Dauphin, F. Goldwasser, B. Blanchet
Journal: Journal of Clinical Oncology (2011)

2581 Background: Sorafenib, an oral multitargeted tyrosine kinase inhibitor, displays a large interindividual variability in its pharmacokinetics. Sorafenib is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterise in vitro sorafenib binding properties to albumin and α1-acid glycoprotein (AAG), then to investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in cancer patients with advanced solid tumors. Methods: The quenching fluorescence method was used to characterize in vitro the sorafenib binding properties. The influence of albuminemia and bilirubinemia on sorafenib disposition was investigated in 54 adult patients receiving single agent sorafenib (200 or 400 mg twice daily). Sorafenib plasma concentrations were assessed at steady state by liquid chromatography. A specific bayesian estimator for sorafenib allowed estimating individual clearance (CL). Results: The estimate of sorafenib dissociation constant (Kd) for albumin was 4-fold lower than that for AAG (0.22 vs 0.90 µM, respectively). In physiological conditions, sorafenib free fraction would increase 1.7-fold whether albuminemia decreased from 45 g/L to 30 g/L. In presence of bilirubin, apparent Kd of sorafenib was approximately 1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In contrast, the presence of fatty acids at molar ratio reachable in clinical settings did not alter sorafenib albumin binding. In clinical settings, median sorafenib dose-standardized AUC was 70.7 mg/L.h (range 26 – 208.8) per 400 mg of sorafenib. In univariate analysis, sex, body mass index, albuminemia and protein C-reactive level were associated with CL (p=0.04, 0.048, 0.008 and 0.05, respectively). In multivariate analysis, albuminemia (p=0.0036) was the single parameter independently associated with CL. Overall, CL was negatively correlated to albuminemia (r=-0.37). Conclusions: The present findings highlight the major influence of albuminemia on sorafenib clearance and therefore on its disposition in adult cancer patients.