tbuckley/cabot-search huggingface dataset:
Abstract 4810: Histone deacetylase 2 is a potential determinant of the sensitivity of hepatocellular carcinoma cells to sorafenib
Authors: Hyung Seok Kim, Jung Woo Eun, Qingyu Shen, Woo Chan Shin, Hee Doo Yang, Sang Yeon Kim, Suk Woo Nam
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the fifth frequently diagnosed cancer and is the second leading cause of cancer death worldwide. Many groups have suggested possible clinical applications for liver cancer therapy but sorafenib, an orally-available kinase inhibitor, is the only standard systematic therapeutics for treatment of hepatocellular carcinoma. However, survival benefit of sorafenib is unsatisfactory due to high level heterogeneity of individual response. We previously reported that histone deacetylase 2 (HDAC2) was deregulated in HCC, and thereby contributed to liver tumorigenesis by enhancing mitotic and metastatic potential of transformed cells. Targeted-disruption of HDAC2 suppressed in vitro and in vivo tumorgigenic potential of HDAC2 in liver cancer. The goal of this study was to investigate whether both sorafenib treatment and HDAC2 inhibition elicit synergistic anti-tumor effect against HCC cells. Here, we showed that sorafenib effectively blocked ERK/MEK and AKT signaling pathway upon EGF stimulation in liver cancer cell lines. Also, we found that valproic acid (VPA), a selective inhibitor of histone deacetylase family I, and sorafenib treatment synergistically evoked liver cancer cell growth retardation. This effect was recapitulated by HDAC2 knockdown with sorafenib treatment and exhibited synergistic effect on apoptotic cell death of liver cancer cell lines, Hep3B and Huh7, compared to single treatment of sorafenib. Our data suggest that combined sorafenib treatment with HDAC2 targeting may provide more benefits toward HCC therapy providing a novel approach for future application in patients with advanced HCC. Citation Format: Hyung Seok Kim, Jung Woo Eun, Qingyu Shen, Woo Chan Shin, Hee Doo Yang, Sang Yeon Kim, Suk Woo Nam. Histone deacetylase 2 is a potential determinant of the sensitivity of hepatocellular carcinoma cells to sorafenib. [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 4810.
Abstract 5088: ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma progression
Authors: Holli A. Loomans, Laura L. Quast, Claudia A. Andl
Journal: Cancer Research (2016)

Abstract Squamous cell carcinomas (SCC) of the head and neck and esophagus pose a substantial public health risk globally. As SCC is often diagnosed in late stage, therapeutic options are limited. A more thorough understanding of the mechanisms involved their progression is needed. One potential mode by which SCCs progress is via Activin A signaling. The downstream effects of Activin A signaling have been primarily characterized as growth inhibiting and anti-angiogenic. However, Activin A is commonly overexpressed in SCC. Therefore, we hypothesized that SCC become insensitive to Activin A stimulation through the dysregulation of the signaling pathway. To model this dysregulation we utilized CRISPR-mediated regulation of ACVRIB (ACVRIB-kd), the necessary type IB receptor to transduce Activin A signaling in three SCC cell lines. Downregulation of ACVRIB enhanced invasiveness in the OSC19 SCC three-dimensional organotypic cultures. Additionally, ACVRIB-kd cells showed significant changes in protein expression, when compared to control. In particular, the correlative markers of SCC aggressiveness and putative downstream Activin A targets, podoplanin and fibronectin, were substantially altered in ACVRIB-kd cells. Integrin expression, particularly integrins β3, α5, and αv, was markedly changed in ACVRIB-kd cells, indicating additional ACVRIB-mediated effects to ECM proteins. We are currently analyzing ACVRIB-kd SCC tumor growth and metastasis in vivo using tongue orthotopic xenografts and subcutaneous flank injections. In conclusion, SCC-specific disruption of Activin A signaling promotes an aggressive phenotype. Re-activation of the canonical Activin A pathway may provide a novel therapeutic strategy to combat SCC. Citation Format: Holli A. Loomans, Laura L. Quast, Claudia A. Andl. ACVRIB-dependent regulation of extracellular matrix protein in squamous cell carcinoma 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 5088.
Abstract 3677: Loss of IRF5 induces spontaneous murine mammary tumorigenesis
Authors: Dan Li, Xiaohui Bi, Corey Goyeneche, Amy Pitler, Betsy Barnes
Journal: Cancer Research (2016)

Abstract Despite significant research efforts, breast cancer is still the most common malignancy in women and the most common cause of cancer death worldwide. A major challenge in breast cancer treatment is disease heterogeneity that is contributed by many factors including intrinsic cell factors, microenvironment, angiogenesis and tumor-specific immune responses. Interferon regulatory factor 5 (IRF5) is a transcription factor that controls inflammatory and immune responses. Analysis of over 3,000 human breast cancer tissues revealed that high expression of IRF5 correlates with increased survival and lower incidence of metastasis, whereas the lower quartile of IRF5 expression is a significant marker of poor prognosis for recurrence-free survival. These data support a tumor suppressor role for IRF5. To examine how loss of IRF5 expression may play a role in spontaneous mammary tumorigenesis, we generated Irf5 knockout (ko) mice in a BALB/C background. In mammary glands harvested from one-year-old female virgin ko mice (n = 15), we found an increased incidence (16%) of mammary carcinoma in situ as compared to their wild-type littermates (4%; n = 18). Of interest, the number of tumor bearing mice was significantly higher (38%) in retired ko female breeders (n = 8); however, there were no abnormalities detected in one-year-old male ko virgins or breeders (n = 6). Cellular and molecular analysis of female ko and wild-type littermates revealed that Irf5 deficiency enhanced mammary epithelial cell proliferation as indicated by an increased number of Ki67 expressing cells, and resulted in abnormal hyperbranching, which may contribute to mammary tumorigenesis. Irf5 ko breeders also showed impaired mammary gland involution after weaning, which has been shown to facilitate mammary tumor formation in humans. Taken together, these findings demonstrate that IRF5 is a gender-specific tumor suppressor in breast cancer. In this ongoing study, we are further investigating the intrinsic and extrinsic (microenvironment) role of IRF5 in mammary tumor initiation and progression. Citation Format: Dan Li, Xiaohui Bi, Corey Goyeneche, Amy Pitler, Betsy Barnes. Loss of IRF5 induces spontaneous murine mammary tumorigenesis. [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 3677.
Abstract 2937: Expression of osteopontin splicing isoforms in prostate cancer cells resistant to docetaxel
Authors: Mariana Concentino Menezes, Amanda O’Neil, Isabella Guimaraes, Letícia Rangel, Etel Rodrigues Pereira Gimba
Journal: Cancer Research (2016)

Abstract Resistance to chemotherapeutic drugs corresponds to main causes of treatment failure. Total osteopontin (OPN) has been described as a gene product involved on chemoresistance, besides activating several aspects of tumor progression. OPN regulates the expression of P-glycoprotein (P-gp) in prostate cancer (PCa) cells, besides promoting apoptosis evasion induced by chemotherapy using paclitaxel and estramustin. These data point OPN as a potential therapeutic target to approaches that could reduce chemotherapy tumor resistance. However, most of this data are related to total OPN. Once OPN suffers alternative splicing, producing 3 isoforms, further investigation should demostrate their specific involvement on chemoresistance. Recent data from our group indicated that OPNb and OPNc splicing isoforms activate PCa tumor progression features. Besides, PCa cells that overexpress these splice variants are more resistant to apoptosis induced by docetaxel (DXT). The current work aims to investigate the expression pattern of OPN splicing isoforms (OPN-SIs) and their relationships in DXT-PCa resistant cells. Total RNA has been extracted from PCa cell lines resistant to DXT (PC3-D8 and PC3-D12) and PC3 control cells with similar cell passages (PC3-Ag). Then, cDNa has been synthesized. OPN-SI expression levels were analyzed by quantitative real time PCR (qRT-PCR) using SYBR Green and isoform specific oligonucleotides. Relative expression levels were calculated using ΔΔCT method. Among the 3 OPN-SIs, we observed that OPNb and OPNc variants are overexpressed in relation to OPNa in DXT-PCa resistant cells PC3-D8 and PC3-D12, when compared to PC3-Ag. PC3-D12 cell line, resistant to higher DXT concentrations, expresses higher levels of OPNc, when compared to the other cell lines. Overall, our data further evidence that OPNb and OPNc overexpression in DXT-PCa resistant cells could be involved on resistance to DXT. Functional assays will be performed in order to investigate the molecular mechanisms by which these OPN-SIs mediate resistance to this chemotherapeutic drug. Citation Format: Mariana Concentino Menezes, Amanda O’Neil, Isabella Guimaraes, Letícia Rangel, Etel Rodrigues Pereira Gimba. Expression of osteopontin splicing isoforms in prostate cancer cells resistant to docetaxel. [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 2937.
Knock-in of a FLT3 Internal Tandem Duplication Mutation Cooperates with a NUP98-HOXD13 Fusion to Generate Acute Myeloid Leukemia
Authors: Sarah M Greenblatt, Li Li, Christopher Slape, Rachel L Novak, Amy S. Duffield, Bao Nguyen, David Huso, Michael J. Borowitz, Peter Aplan, Donald Small
Journal: Blood (2011)
Effect of intensive insulin therapy on glutathione synthesis rate in cancer patients with stress hyperglycemia after major surgery.
Authors: M. De Cicco, M. Malafronte, R. Lazzarini, P. Spessotto, B. Massolino, D. Fantin, C. A. Bertuzzi, A. Veronesi, G. Biolo
Journal: Journal of Clinical Oncology (2010)

e19593 Background: The glutathione system plays an essential role in antioxidant defense. We assessed the effects of intensive insulin treatment on glutathione synthesis rate and redox balance in non-diabetic cancer patients developing stress hyperglycemia after major surgery. Methods: We have studied 10 cancer patients after abdominal radical surgery combined with intraoperative radiation therapy admitted to intensive care unit and receiving total parenteral nutrition. In each patient, a 24-hr period of insulin-mediated (96±23 units/24 hrs) tight euglycemia (5.9±0.3 mmol/L) preceded (n=5) or followed (n=5) a 24-hr control period of traditional insulin treatment (29±11 units/24 hrs) with moderate hyperglycemia (9.0±0.4 mmol/L) on the first and second day after surgery, according to a crossover design with randomized sequence of treatments. Systemic oxidative stress, as plasma concentrations of thiobarbituric acid reactive substances (TBARS), and erythrocyte glutathione synthesis rate, by primed-constant infusion of the stable isotope L-[2H2] cysteine, were assessed at the end of each 24-hr period of euglycemia and of hyperglycemia. Data were analyzed by means of ANOVA (repeated measures with interactions). Results: There was no significant treatment sequence effect for any parameter. Euglycemia as compared to moderate hyperglycemia was associated with higher (p<0.01) erythrocyte glutathione synthesis rate (2.5±0.4 vs. 1.1±0.3 mmol L-1 day-1) and lower (p=0.04) plasma TBARS concentrations (2.2±0.2 vs. 2.9±0.4 nmol/L). Insulin-mediated changes in glutathione synthesis rate inversely correlated with changes in plasma TBARS concentrations (Spearman's r = −0.67; p=0.03). Conclusions: Intensive insulin treatment increases erythrocyte glutathione synthesis leading to decreased oxidative stress in cancer patients developing stress hyperglycemia after major surgery. No significant financial relationships to disclose.
Abstract 3049: Arachidonate 12-lipoxygenase contributes to radiation-induced type II pneumocyte senescence and fibrosis
Authors: Eun Joo Chung, Luca F. Valle, Ayla O. White, Deborah E. Citrin
Journal: Cancer Research (2016)

Abstract Introduction: Ionizing radiation (IR) is commonly used in the treatment of thoracic malignancies. Exposure of adjacent normal lung may result in lung injury and fibrosis. Recently, we reported that accelerated senescence of type II pneumocytes, the alveolar stem cell, results in parynchymal depletion and precedes pulmonary fibrosis. Arachidonate 12-lipoxygenase (12-LOX) oxidizes arachidonic acid to form 12-Hydroxyeicosatetraeonic acid (12-HETE), a pro-inflammatory mediator. Increased expression of ALOX-12 has previously been associated with aging. We hypothesized that mice deficient in ALOX-12 would be resistant to IR induced fibrosis and senescence. Methods: C57/Bl6J (WT) and Alox12 homozygous knockout (Alox12-KO) mice (n&amp;gt;3 per group) were exposed to thoracic IR (0Gy, 5Gy, 17.5Gy, 5×5Gy, or 6×5Gy). Fibrotic foci were identified with aniline blue staining of fixed lung sections. Levels of 12-LOX mRNA and protein were assessed in WT lungs after IR with microarray, quantitative PCR, and western blotting. In vitro studies with primary murine pneumocyte cultures and A549 cells included staining for senescence associated β-galactosidase activity and western blotting for NOX4, p21, and PML following IR and 12-HETE treatment. Results: A significant increase in 12-LOX mRNA and protein was observed in murine lungs exposed to fibrogenic doses of IR (17.5 Gy, 5×5 Gy and 5×6 Gy) compared to low dose IR (5 Gy) or controls (0 Gy). 12-LOX deficiency significantly reduced fibrotic foci in murine lungs receiving fibrogenic doses of thoracic IR (6×5 Gy) at 18 weeks. Treatment of murine primary pneumocytes with 12-HETE (1 and 150 nM) increased the rate of pneumocyte senescence (2.1 fold). Treatment of murine primary pneumocytes with 12-HETE increased the expression of NOX4 (a mediator of superoxide generation), p21, and PML (senescence markers), paralleling increases observed after IR. Similarly, human type II pneumocyte A549 cells exhibited increased 12-LOX expression in β-galactosidase-stained senescent cells at 3 days after IR. Conclusion: These studies identify 12-LOX as a critical mediator in radiation lung fibrosis and type II pneumocyte senescence. 12-LOX may serve as a novel therapeutic target in mitigating IR-induced lung fibrosis. Citation Format: Eun Joo Chung, Luca F. Valle, Ayla O. White, Deborah E. Citrin. Arachidonate 12-lipoxygenase contributes to radiation-induced type II pneumocyte senescence and fibrosis. [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 3049.
Abstract 3640: Validation of qBiomarker as an accurate and efficient mutation detection method in a comprehensive analysis of patient-derived tumor xenografts
Authors: Mariana Brait, Evgeny Izumchenko, Luciane Kagohara, Samuel Long, Piotr Wysocki, Brian Faherty, Elana Fertig, Tin Khor, Elizabeth Bruckheimer, Gilson Baia, Daniel Ciznadija, Ido Sloma, Ido Ben-Zvi, Keren Paz, David Sidransky
Journal: Cancer Research (2016)

Abstract Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted Next Generation Sequencing (NGS) - based approaches provide accurate results and offer promising diagnostic capabilities, there are still limitations which impede their adoption for large-scale population-based screening. There is a pressing clinical need for a well-validated, rapid, cost-effective and accurate mutation profiling system with optimal analytical performance in patient specimens. Given their speed, and cost-effectiveness, real-time, quantitative qPCR mutation detection techniques are well suited for the clinical environment. The novel qBiomarker somatic mutation PCR array has high sensitivity and shorter turnaround times compared to other methods. However a direct comparison to existing viable alternatives is required to assess its true potential and limitations. In this study, we extensively evaluated a panel of 117 patient-derived tumor xenografts (PDX) by the qBiomarker array and directly compared its efficacy with that of other routinely used methods for mutation detection, including Ion AmpliSeq sequencing, whole exome sequencing (WES), and ultra-sensitive droplet digital PCR (ddPCR) genotyping. Our comprehensive analysis demonstrates that qBiomarker's performance is on par with that of other routinely used but more complex, labor-intensive and expensive methods of cancer mutation detection, and provides a foundation for advancing the adoption of qBiomarker assay for cancer driving mutation profiling in clinical diagnostics. Furthermore, a large-scale direct comparison of different mutation detection approaches will lead to informed choice of screening methodologies, especially in lower budget conditions or timeframe limitations. Citation Format: Mariana Brait, Evgeny Izumchenko, Luciane Kagohara, Samuel Long, Piotr Wysocki, Brian Faherty, Elana Fertig, Tin Khor, Elizabeth Bruckheimer, Gilson Baia, Daniel Ciznadija, Ido Sloma, Ido Ben-Zvi, Keren Paz, David Sidransky. Validation of qBiomarker as an accurate and efficient mutation detection method in a comprehensive analysis of patient-derived tumor xenografts. [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 3640.
Broncho-Alveolar Lavage and Lung Biopsy in Patients with Hematological Malignancy and Hematopoietic Stem Cell Transplantation Recipients: A Systematic Review and Meta-Analysis
Authors: Deepak Chellapandian, Thomas Lehrnbecher, Bob Phillips, Brian T. Fisher, Theoklis E Zaoutis, William J. Steinbach, Joseph Beyene, Lillian Sung
Journal: Blood (2014)
Statins to Reduce Acute Kidney Injury After Cardiac Surgery
Authors: Pingping Yang, Gaosi Xu
Journal: JAMA (2016)

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Abstract 3377: Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy
Authors: Marta Cesca, Lavinia Morosi, Alexander Berndt, Ilaria Fuso Nerini, Alessandra Decio, Massimo Zucchetti, Raffaella Giavazzi
Journal: Cancer Research (2016)

Abstract Angiogenesis inhibitors have shown antitumor efficacy when combined with chemotherapy. It has been proposed that this potentiation is related to better drug delivery to the tumor due to improved vessel functionality. This work combined classical pharmacokinetics and imaging analysis to study the delivery and distribution of paclitaxel after bevacizumab in ovarian cancer. The study was conducted on ovarian cancer models (A2780-1A9 and IGROV-1) xenografted orthotopically under the bursa of the nude mouse ovary. Mice bearing tumors in the ovary, treated with bevacizumab (150μg/mouse) and 24 hours later with paclitaxel (60mg/kg), were sacrificed and tumor excised for analysis, or monitored for anti-tumor activity. Paclitaxel spatial distribution after bevacizumab was analyzed by MALDI-Mass Spectrometry Imaging (MALDI-MSI) on frozen tumor slices, and compared with adjacent histochemical images stained for CD31 (vessel analysis) and Ki-67 (proliferation/necrosis); total paclitaxel in tumor homogenates, liver and plasma was evaluated by high-performance liquid chromatography (HPLC). Tumor growth of A2780-1A9 and IGROV-1, carrying the firefly luciferase gene luc2, was monitored by Bioluminescence imaging (BLI) and survival recorded. Bevacizumab decreased tumor vessel number/size compared to vehicle treated mice, but potentiated the antitumor activity of paclitaxel in both models. MALDI-MSI showed that after bevacizumab, paclitaxel was more homogenously distributed and mainly in actively proliferating areas of the tumor where vessels were uniformly diffused, despite paclitaxel concentration did not increase after antiangiogenic drug. No changes in paclitaxel systemic exposure was found in normal tissue. These findings suggest that a more uniform distribution of paclitaxel in the tumor of the mouse ovary is responsible for the better antitumor activity of the combination. A.D. and I.F.N. are the recipients of a fellowship from the Italian Foundation for Cancer Research (FIRC). Citation Format: Marta Cesca, Lavinia Morosi, Alexander Berndt, Ilaria Fuso Nerini, Alessandra Decio, Massimo Zucchetti, Raffaella Giavazzi. Bevacizumab-improved distribution of paclitaxel in ovarian cancer xenografts potentiates antitumor efficacy. [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 3377.