tbuckley/cabot-search huggingface dataset:
The use of stand-alone fully covered self-expandable metallic stents for drainage of walled-off necrosis or pseudocyst may lead to poor results
Authors: Bulent Odemis, Erkin Oztas, Muhammet Akpinar, Sabite Kacar, Ufuk Kuzu, Mustafa Ozdemir
Journal: Endoscopy (2016)

In current practice, endoscopic transmural drainage is the preferred method for the treatment of symptomatic walled-off necrosis and pseuodocysts in patients with acute pancreatitis [1]. In order to maintain a fistulous tract between these lesions and the gut lumen, fully covered self-expandable metallic stents (FCSEMS) and/or plastic pigtail stents can be used. The migration of FCSEMS to the gut lumen can lead to the disconnection of the cavity from the gut lumen, abscess development in the cavity, and life-threatening septic complications.
Abstract 2275: Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC
Authors: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu
Journal: Cancer Research (2016)

Abstract Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is known to regulate cell proliferation and drive hepatocellular carcinoma (HCC) formation; however, the underlying mechanisms linking gene expression and tumor formation remain obscure. In this study, we showed that ISX transcriptionally activates E2F1 expression and related oncogenic activity by directly binding to its promoter region. Mechanistically, forced ISX expression upregulated the expression and nucleus translocation of the E2F1-DP1 complex phosphorylated by the cyclin D1-CDKs complex, which promoted oncogenic activities of ISX-E2F1 axis in hepatoma cells. In addition, co-expression of both ISX and E2F1 significantly promoted cell proliferation and anti-apoptotic signals instead of apoptosis and autophagy induced by the tumor suppressors p53 and RB1. In contrast, short hairpin RNA-mediated attenuation of ISX and E2F1, respectively, in hepatoma cells decreased cell proliferation and malignant transformation in vitro and in vivo. The mRNA expression was compared in 238 paired specimens of HCC and adjacent normal tissues, and E2F1, as an expression of ISX, pathologically exhibited a tumor-specific expression pattern and was highly correlated with ISX expression, patient survival time, progression stage, and poor prognosis. Taken together, our results highlight that E2F1 is an important downstream gene of ISX in hepatoma progression. Citation Format: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu. Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC. [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 2275.
Abstract 378: Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309
Authors: Karin Jorga, Debora Schmitz, Natasa Cmiljanovic, Doriano Fabbro, Sasa Dimitrijevic
Journal: Cancer Research (2016)

Abstract Introduction PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for the treatment of solid tumors and hematological malignancies. Eighty mg PQR309 given once daily (q.d.) has been established as the MTD in patients with advanced solid cancers. This dose and regimen was associated with plasma concentrations that were pharmacologically active in pre-clinical experiments. However, there is emerging evidence that continuous inhibition of PI3K/mTOR may not be needed to achieve the full effect of PQR309 on tumor growth inhibition and therefore further intermittent dosing regimens will be explored. Methods In vivo xenograft studies in nude male rats bearing PC3-derived tumors were conducted with continuous and intermittent dosing schedules to estimate effective plasma concentrations. Pharmacokinetic (PK) data from cancer patients were used to establish a 2-compartment PK model with first order absorption. The model was applied to simulate PK profiles after various intermittent dosing schedules including 2 daily administrations followed by a 5 day wash-out period in a 7 day cycle (2 days ON/5 days OFF) and a regimen with administrations on days 1 and 4 in a 7 day cycle (eg MON/THUR). Results A maximum plasma concentration (Cmax) of 800-1200ng/mL PQR309 and an impulse interval of 72 hours or less was associated with maximum effect in the rat xenograft model. In rats PQR309 is rapidly eliminated from plasma but in humans the compound has an elimination half-life of about 40 hours and accumulates upon multiple dosing. The applied model predicts that PQR309 administration given 2 days ON/5 days OFF will build up drug exposure to reach levels that strongly inhibit the targeted signalling pathways. During the 5 day wash-out period, PQR309 levels will decrease significantly, thereby reducing the probability of adverse events. For the alternative dosing regimen MON/THUR, the model predicts a sharp Cmax lasting for a few hours followed by a decrease in drug levels over the following 3 or 4 days, thus minimizing accumulation and drug exposure that could lead to adverse events. Conclusions Both intermittent regimens are expected to strongly inhibit the targeted signalling pathways with high transient concentrations around Cmax followed by wash-out periods for healthy tissue recovery to optimize the benefit/risk of the compound. These regimens are currently being explored in clinical studies. Citation Format: Karin Jorga, Debora Schmitz, Natasa Cmiljanovic, Doriano Fabbro, Sasa Dimitrijevic. Exploring intermittent dosing schedules for the Pan PI3K/mTor inhibitor PQR309. [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 378.
School Siting Near Industrial Chemical Facilities: Findings from the U.S. Chemical Safety Board’s Investigation of the West Fertilizer Explosion
Authors: Veronica A. Tinney, Jerad M. Denton, Lucy Sciallo-Tyler, Jerome A. Paulson
Journal: Environmental Health Perspectives (2016)

The U.S. Chemical Safety and Hazard Investigation Board (CSB) investigated the 17 April 2013 explosion at the West Fertilizer Company (WFC) that resulted in 15 fatalities, more than 260 injuries, and damage to more than 150 buildings. Among these structures were four nearby school buildings cumulatively housing children in grades kindergarten-12, a nursing care facility, and an apartment complex. The incident occurred during the evening when school was not in session, which reduced the number of injuries.The goal of this commentary is to illustrate the consequences of siting schools near facilities that store or use hazardous chemicals, and highlight the need for additional regulations to prevent future siting of schools near these facilities.We summarize the findings of the CSB's investigation related to the damaged school buildings and the lack of regulation surrounding the siting of schools near facilities that store hazardous chemicals.In light of the current lack of federal authority for oversight of land use near educational institutions, state and local governments should take a proactive role in promulgating state regulations that prohibit the siting of public receptors, such as buildings occupied by children, near facilities that store hazardous chemicals.Tinney VA, Denton JM, Sciallo-Tyler L, Paulson JA. 2016. School siting near industrial chemical facilities: findings from the U.S. Chemical Safety Board's investigation of the West Fertilizer Explosion. Environ Health Perspect 124:1493-1496; http://dx.doi.org/10.1289/EHP132.
Abstract 3547: CEBPD induces apoptosis through autophagy in metformin-treated HCC
Authors: I P. Lin.
Journal: Cancer Research (2016)

Abstract The patients with hepatocellular carcinoma (HCC) face the risk of cancer relapse or liver dysfunction. Metformin (Met), a first-line drug of type 2 diabetes, has been proved that it could induce G1 arrest and prevent or inhibit HCC. Previously, we demonstrated that the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) plays a tumor suppressor and is responsive to many anticancer drugs in HCC. In this study, we found that Met could induce autophagy, growth arrest and further apoptosis in Huh7 cells. Met enhanced CEBPD expression via stabilizing its protein stability. The loss of CEBPD attenuated the Met-induced autophagy, growth arrest and apoptosis. Importantly, in addition to increasing P27 and down-regulating cyclin D1, CEBPD also contributed the increases of LC3B and ATG3 and LC3 puncta formation. We revealed a novel involvement of CEBPD in Met-induced growth arrest, apoptosis and autophagy of liver cancer cells through regulating p27, cyclinD1, LC3B and ATG3. Citation Format: I P. Lin. CEBPD induces apoptosis through autophagy in metformin-treated HCC. [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 3547.
Abstract 1049: Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust <i>in vivo</i> efficacy and increased therapeutic index with niacin supplementation
Authors: Maria Quanz, Claudia Merz, Andreas Bernthaler, Stefan Kaulfuss, Anja Richter, Marcus Bauser, Andrea Haegebarth
Journal: Cancer Research (2016)

Abstract Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and cofactor for a number of cellular processes including genomic stability and epigenetic regulation. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme in NAD+ salvaging from nicotinamide. Many tumor cells have an increased need for NAD+ and are therefore highly sensitive to NAMPT inhibition. We have developed a selective and potent small molecule inhibitor, Cmpd1, which inhibits the NAMPT enzyme with sub-nanomolar potency. In cells, Cmpd1 treatment leads to an almost complete reduction of both NAD- and ATP-levels, followed by the induction of cell death. In order to identify sensitive cancer subtypes and associated biomarkers, we analyzed cell sensitivity to NAMPT inhibition in a panel of 240 cell lines. Small cell lung cancer and hematological malignancies were particularly sensitive to NAMPT inhibition. Overall, expression levels of NAMPT and NAD+ consuming enzymes correlated well with sensitivity to NAMPT inhibition. In order to investigate the effect of niacin on the antiproliferative effect of NAMPT inhibition across the cell panel, we further analyzed the cell sensitivity in the presence of niacin. Cells with a functional Preiss-Handler pathway can generate NAD+ from niacin, independent of NAMPT. We found that the antiproliferative effect of Cmpd1 was neutralized by niacin in 60% of the analyzed cells. The mRNA levels of nicotinate phosphoribosyltransferase 1 (NAPRT1), a central enzyme of the Preiss-Haendler pathway, predicted well the niacin rescue status of the cells. In vivo, niacin supplementation led to an at least 10-fold increase in the maximum tolerated dose of Cmpd1 in mice. Antitumor efficacy of Cmpd1 was abolished by niacin supplementation in xenografts derived from NAPRT1 expressing cells, but not in NAPRT1-deficient models. These data demonstrate that the therapeutic index of NAMPT inhibitors may be increased in NAPRT1-deficient tumors by niacin supplementation. Citation Format: Maria Quanz, Claudia Merz, Andreas Bernthaler, Stefan Kaulfuss, Anja Richter, Marcus Bauser, Andrea Haegebarth. Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation. [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 1049.
Abstract 2004: Nucleation of transcriptional super-enhancers at tumor oncogenes by small insertions
Authors: Brian J. Abraham, Denes Hnisz, Abraham S. Weintraub, Nicholas Kwiatkowski, Charles H. Li, Sunniyat Rahman, Zhaodong Li, Tong Ihn Lee, A Thomas Look, Marc Mansour, Richard A. Young
Journal: Cancer Research (2016)

Abstract Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics[1,2,3,4]. Super-enhancers are acquired by cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs)[5]. In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 oncogene. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify short DNA sequences missing from reference genomes. We have found and catalogued many additional genomic insertions in 80 additional cancers. An additional insertion has been functionally characterized and determined to be a bona fide enhancer-nucleating insertion that exists in patient genomes. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements. [1] Hnisz, Abraham, Lee, et al., Cell 2013 [2] Loven, Hoke, Lin, et al., Cell 2013 [3] Kwiatkowski, et al., Nature, 2014 [4] Wang, et al., Cell, 2015 [5] Mansour et al., Science 2014 Citation Format: Brian J. Abraham, Denes Hnisz, Abraham S. Weintraub, Nicholas Kwiatkowski, Charles H. Li, Sunniyat Rahman, Zhaodong Li, Tong Ihn Lee, A Thomas Look, Marc Mansour, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes by small insertions. [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 2004.
Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis
Authors: Meritxell Nus, Beatriz Martínez-Poveda, Donal MacGrogan, Rafael Chevre, Gaetano D’Amato, Mauro Sbroggio, Cristina Rodríguez, José Martínez-González, Vicente Andrés, Andrés Hidalgo, José Luis de la Pompa
Journal: Cardiovascular Research (2016)

To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis.We have generated a mouse model of endothelial-specific (Cdh5-driven) depletion of the Notch effector recombination signal binding protein for immunoglobulin kappa J region (RBPJ) [(ApoE-/-); homozygous RBPJk conditional mice (RBPJflox/flox); Cadherin 5-CreERT, tamoxifen inducible driver mice (Cdh5-CreERT)]. Endothelial-specific deletion of RBPJ or systemic deletion of Notch1 in athero-susceptible ApoE-/- mice fed a high-cholesterol diet for 6 weeks resulted in reduced atherosclerosis in the aortic arch and sinus. Intravital microscopy revealed decreased leucocyte rolling on the endothelium of ApoE-/-; RBPJflox/flox; Cdh5-CreERT mice, correlating with a lowered content of leucocytes and macrophages in the vascular wall. Transcriptome analysis revealed down-regulation of proinflammatory and endothelial activation pathways in atherosclerotic tissue of RBPJ-mutant mice. During normal Notch activation, Jagged1 signalling up-regulation in endothelial cells promotes nuclear translocation of the Notch1 intracellular domain (N1ICD) and its physical interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This N1ICD-NF-κB interaction is required for reciprocal transactivation of target genes, including vascular cell adhesion molecule-1.Notch signalling pathway inactivation decreases leucocyte rolling, thereby preventing endothelial dysfunction and vascular inflammation. Attenuation of Notch signalling might provide a treatment strategy for atherosclerosis.
Comparison of hypofractionated high-dose intensity-modulated radiotherapy schedules for prostate cancer: Results from the phase III randomized CHHiP trial (CRUK/06/016).
Authors: David P. Dearnaley, Isabel Syndikus, Helen Mossop, Alison J. Birtle, DJ Bloomfield, Clare Cruickshank, John Graham, Shama Hassan, Vincent Khoo, John P. Logue, Helen Mayles, Julian Money-Kyrle, Olivia Frances Naismith, Miguel Panades, Helen Patterson, Christopher D Scrase, John Staffurth, Jean Tremlett, Clare Griffin, Emma Hall
Journal: Journal of Clinical Oncology (2016)

2 Background: We aimed to explore the dose response relationship for two 3 Gray (Gy) hypofractionated radiotherapy (hRT) schedules for localised prostate cancer (PCa). Methods: hRT schedules of 60Gy/20 fractions (f) and 57Gy/19f were compared with conventional RT (cRT) 74Gy/37f; iso-effective for alpha-beta ratios of 2.5Gy and 1.5Gy respectively. The trial was powered to demonstrate non-inferiority between each hRT schedule and cRT, with 3,213 patients (pt) needed to rule out 5% inferiority (80% power, 1-sided alpha 5%) assuming 70% event-free rate in cRT, corresponding to a critical hazard ratio (HR) of 1.21. The trial was not formally powered to directly compare the two hRT schedules. Pt with N0 T1b-T3a localised PCa were randomized (1:1:1 ratio). The primary endpoint was PCa progression (freedom from biochemical failure by Phoenix consensus guidelines or PCa recurrence). Acute toxicity was assessed up to 18 weeks post treatment and late side effects to 5 years (yr) by RTOG, LENT-SOM and patient reported outcomes (PROs). Results: 3,216 pts were randomized between 2002 and 2011; 1,065 (74Gy), 1,074 (60Gy), 1,077 (57Gy). Baseline characteristics were well balanced across groups: median age 69 yr; NCCN risk group 15% low, 73% intermediate, 12% high. With median follow up 5.2yr, 5yr progression-free rate (95% CI) was 74Gy: 88.3% (86.0%, 90.2%); 60Gy: 90.6% (88.5%, 92.3%), 57Gy: 85.9 (83.4, 88.0); HR 60/74 : 0.83, 90% CI (0.68, 1.03), HR 57/74 : 1.20, 90% CI (0.99, 1.45). Significantly more events were observed with 57Gy compared to 60Gy; HR 57 /60 : 1.44, 90% CI (1.18, 1.75), log-rank p=0.003. No significant difference in acute RTOG bladder or bowel toxicity was observed between hRT schedules. Late toxicity profile was favorable; with grade 2+ RTOG bladder (60Gy: 16/960 (1.7%); 57Gy: 11/962 (1.1%), p=0.34) and bowel (60Gy: 28/960 (2.9%); 57Gy: 17/962 (1.8%), p=0.10) toxicity at 2yr. Analysis of LENT-SOM and PROs supported these results. Conclusions: With 5 yr follow-up treatment with a 3Gy schedule of 60Gy/20f shows improved treatment efficacy compared to 57Gy/19f and is non-inferior to 74Gy/37f with a similar low level of acute and late normal tissue damage. Clinical trial information: ISRCTN97182923.
Abstract 4664: Co-targeting HGF-cMET signaling with MEK inhibitors in metastatic uveal melanoma
Authors: Hanyin Cheng, Ken Kageyama, Timothy Purwin, Connie Liao, Mizue Terai, Takami Sato, Andrew Aplin
Journal: Cancer Research (2016)

Abstract Metastatic uveal melanoma (UM) patients usually die within one year, emphasizing an urgent need to develop new treatment strategies. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in cutaneous melanoma patients but have limited efficacy in UM patients. Our previous work show that HGF-cMET signaling provides resistance to MEK inhibitors in metastatic UM cells. In this study, we further investigated the mechanisms of HGF-driven resistance to MEK inhibitors in metastatic UM cells. Cellular signaling pathway analysis was carried out to determine the role of downstream Bcl2 family members in overcoming trametinib-mediated apoptosis by HGF in metastatic UM cells. A new class of clinical grade cMET antibody and inhibitor were tested for their capacity to revert the resistance to trametinib mediated by HGF and tumor microenvironment. Selective inhibitors were utilized to determine the PI3K isoform dependency of metastatic UM cells in HGF-mediated protection against trametinib in metastatic UM cells. We demonstrate that the expression of two BH3-only family proteins, Bim-EL and Bmf, is upregulated in trametinib treated cells, but returns to basal levels upon HGF treatment in these cells. Targeting HGF-cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. PI3Kβ-sparing inhibitor GDC0032 effectively blocks HGF-induced AKT phosphorylation and HGF-mediated resistance in trametinib treated cells in growth assays. In conclusion, our data suggest that HGF promotes resistance to MEK inhibitors through modulating Bim-EL and Bmf expression in UM cells. Our data also support the notion that selectively blocking PI3K isoform activities or cMET signaling may delay the onset of resistance to MEK inhibitors provided by tumor microenvironment in metastatic uveal melanoma. Citation Format: Hanyin Cheng, Ken Kageyama, Timothy Purwin, Connie Liao, Mizue Terai, Takami Sato, Andrew Aplin. Co-targeting HGF-cMET signaling with MEK inhibitors in metastatic uveal 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 4664.
Abstract 3115: Characterization of CDCA1 protein as a novel prognostic biomarker and therapeutic target for oral cancer
Authors: Thang Manh Phung, Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yoshinori Murakami, Yataro Daigo
Journal: Cancer Research (2017)

Abstract Oral cavity carcinoma (OCC) is one of the most common causes of cancer-related death worldwide. Current therapies for OCC still show poor clinical outcome with five-year survival rate of less than 63%. Therefore, next generation biomarkers and therapeutic strategies for OCC are eagerly awaited. We selected genes that were specifically overexpressed in the majority of OCC using our gene expression profile database, and identified cell division cycle associated 1 (CDCA1) that appeared to encode nuclear protein as a candidate. Immunohistochemical analysis using tissue microarray covering 99 OCC tissues detected that CDCA1 protein was expressed in 67 cases of 99 OCC tissues (68%), but not in normal oral epithelia. In addition, high levels of CDCA1 protein expression was significantly associated with poor prognosis for OCC patients (P = 0.0244 by log-rank test). Furthermore, knockdown of CDCA1 expression by siRNAs significantly inhibited the growth of tumor cells. Moreover, flow cytometric analysis, multiple apoptosis assays, and live cell imaging experiment revealed that CDCA1 could be important for the growth and survival of OCC cells, probably through the regulation of mitotic prophase and/or apoptosis. Our findings suggest that CDCA1 is likely to be a novel prognostic biomarker and a therapeutic target for OCC patients. Citation Format: Thang Manh Phung, Atsushi Takano, Yoshihiro Yoshitake, Masanori Shinohara, Yoshinori Murakami, Yataro Daigo. Characterization of CDCA1 protein as a novel prognostic biomarker and therapeutic target for oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3115. doi:10.1158/1538-7445.AM2017-3115