tbuckley/cabot-search huggingface dataset:
Abstract 2734: Ethanol potentiates tobacco smoke carcinogens-induced MAPK activation
Authors: Manoj K. Pandey, Jagat J. Mukherjee, Dhimant H. Desai, Shantu G. Amin, Subodh Kumar
Journal: Cancer Research (2015)

Abstract Alcohol consumption along with smoking is a well-known health hazard to human. How alcohol consumption potentiates the smoking mediated hazard is not clear. Previously we reported that DNA damage caused by tobacco smoke carcinogen (+/-) anti-benzo[a]pyrene-7, 8-diol-9,10-epoxide [BPDE] is responded by cells through induction of cell growth inhibition in different cell lines. Here we observed that ethanol (EtOH) treatment at physiologically relevant concentration (60mM) increases the DNA synthesis in DNA damaging carcinogen (BPDE) treated cells. BPDE treatment of cells elicits G1-S cell cycle arrest, but EtOH does not have any significant modulating effect of G1-S arrest, indicating increased DNA synthesis by EtOH is due to modulation of some other signaling event(s). We observed that EtOH co-treatment/ pretreatment potentiates BPDE induced phosphorylation and activation of extracellular regulated kinase 1/2 (ERK1/2). Interestingly, treatment of cells with MEK1 inhibitor (PD09059) significantly reduced EtOH's ability to increase DNA synthesis in BPDE treated cells. All together, these findings suggest that the ability of EtOH to potentiate BPDE-induced ERK activation may potentiates PAH-induced tumorigenesis. [Supported by NIH grant # R03 ES021779]. Citation Format: Manoj K. Pandey, Jagat J. Mukherjee, Dhimant H. Desai, Shantu G. Amin, Subodh Kumar. Ethanol potentiates tobacco smoke carcinogens-induced MAPK activation. [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 2734. doi:10.1158/1538-7445.AM2015-2734
Phase I/II pharmacokinetic and pharmacodynamic study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor, in patients with advanced pancreatic cancer receiving treatment with gemcitabine.
Authors: R. K. Ramanathan, M. Chadha, V. Gressler, S. Shah, D. Loury, A. Hamdy, E. Hedrick, A. A. Khorana
Journal: Journal of Clinical Oncology (2011)

e14610 Background: PCI-27483 is a selective inhibitor of FVIIa, a protease activated by interaction with tissue factor (TF). TF upregulation in tumor cells correlates with angiogenesis. Activation of PAR2 receptors by the TF:FVIIa complex induces upregulation of IL-8 and VEGF. PCI-27483 inhibited growth of human pancreatic tumors in animals at a 2.5x to 3.0x change in prothrombin time. Clinically, INR is used as an easily measured PD marker. PK/INR relationships observed in a Phase I study in healthy volunteers were used to select the initial doses for the current study. Methods: Patients (pts) with locally advanced or metastatic pancreatic cancer, ECOG performance status 0-1, and normal coagulation were enrolled. All pts in phase I and II receive gemcitabine (G) as a 30-min IV infusion at a dose of 1,000 mg/m2 x3 every 4wks. PCI-27483 is administered bid by SC injection. In phase I, doses of PCI-27483 were intra-patient escalated (0.8 to 1.2 to 1.5 mg/kg) over 4 to 8 wks. The targeted peak INR, measured 2 h postdose, was 3.0. Phase I pts receiving 80% of planned doses during in first 8 wks were considered evaluable. In phase II, pts are being randomized to receive G ± PCI-27483. Results: The phase I potion is completed with 8 pts enrolled and 5 pts evaluable. Highest dose of PCI-27483 achieved was 0.8 mg/kg for 2 pts, 1.2 mg/kg for 3 pts and 1.5 mg/kg for 3 pts. Hematologic grade 3 toxicities included anemia (n=2) and thrombocytopenia (n=1). Other grade 3 toxicities included elevated INR (n = 4) and GI hemorrhage (n = 1). Target peak and trough INR values were achieved at 1.2 mg/kg. INR values correlated with plasma concentrations; plasma t1/2 was 7.7 h. No thrombotic episodes occurred. Assessment of 5 evaluable pts: 3 stable disease (SD) for ≥30 wks (first pt SD for 56 wks). Conclusions: In the phase I portion, PCI‐27483 was well tolerated at doses up to 1.5 mg/kg bid with G given at 1,000 mg/m2. Sustained SDs occurred and INRs were within the expected range. In phase II, pts (n=40) are being randomized to receive G ± PCI-27483 at a dose of 1.2 mg/kg bid.
Resuscitation Decisions of Extremely Premature Infants at the Limits of Viability: Defining Best Interests
Authors: Jennifer E. deSante-Bertkau, Beth Haberman
Journal: The American Journal of Bioethics (2016)

A comprehensive analysis of this case must examine the roles and obligations of both the pregnant woman and the medical team. Once the ethics consultant has clarified the infant's prognosis, he or ...
Abstract 1064: RASSF10 suppresses colorectal cancer growth by activating p53 signaling and sensitizes colorectal cancer cell to docetaxel
Authors: Jing Guo, Yage Yang, Yunsheng Yang, Enqiang Linghu, Qimin Zhan, Malcolm V. Brock, James G. Herman, Bingyong Zhang, Mingzhou Guo
Journal: Cancer Research (2015)

Abstract RASSF10 has previously been reported to be frequently methylated in a number of malignancies. To understand the importance of RASSF10 inactivation in colorectal carcinogenesis, eight colorectal cancer cell lines, 89 cases of primary colorectal cancer and 5 cases of normal colorectal mucosa were examined. Methylation specific PCR, western blot, siRNA, gene expression array and xenograft mice were employed. The expression of RASSF10 was was regulated by promoter regional methylation in colorectal cancer cells. RASSF10 was methylated in 60.7% (54/89) of primary colorectal cancers and was positively associated with tumor stage (p&amp;lt;0.05) and metastasis (p&amp;lt;0.05). Restoration of RASSF10 led to inhibition of colorectal cancer cell proliferation in vitro and in vivo and increased apoptosis. Gene expression arrays discovered RASSF10 inhibition of MDM2 expression as a mediator of these effects, which was confirmed with RT- PCR and western blot. RASSF10 was shown to activate P53 signaling in RKO and HCT116 cells after UV exposure, and sensitized these cells to docetaxel. In conclusion, our study demonstrates RASSF10 is frequently methylated in human colorectal cancer leading to loss of expression. RASSF10 normally suppresses human colorectal cancer growth by activating P53 signaling in colorectal cancer, and restored expression sensitizes colorectal cancer to docetaxel. Citation Format: Jing Guo, Yage Yang, Yunsheng Yang, Enqiang Linghu, Qimin Zhan, Malcolm V. Brock, James G. Herman, Bingyong Zhang, Mingzhou Guo. RASSF10 suppresses colorectal cancer growth by activating p53 signaling and sensitizes colorectal cancer cell to docetaxel. [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 1064. doi:10.1158/1538-7445.AM2015-1064
440. Extreme Polyvalency Induces Potent Cross-Clade Cellular and Humoral Responses in Rabbits and Non-Human Primates
Authors: Megan Wise, Kar Muthumani, Janess Mendoza, Jian Yan, Anna Slager, Kim Kraynyak, David Montefiori, Celia LaBranche, Kate Broderick, Matthew Morrow, Niranjan Sardesai, David Weiner
Journal: Molecular Therapy (2016)

There is a pressing need to determine possible unique vaccine combinations of Envs which induce enhanced breadth and functional antibody responses. Due to the ease of manufacturing and formulation, we sought to determine if increased breadth within a vaccine correlates with robust and broad responses. We have developed over 40 different DNA plasmids expressing consensus as well as primary Envs. We have shown that each of these plasmids are able to induce both cellular and humoral responses in mice. Different combinations of Envs were testing in rabbits to further characterize the humoral responses and explore neutralization. Rabbits immunized with clusters of clade A transmitter founder (TF) gp160 DNA induced cross-clade binding titers with limited neutralization. Including TF Envs from different clades, increased binding titers as well as neutralization breadth and potency. Formulating the gp160s to be administered to the same site induced quicker seroconversion than delivering the Envs at separate sites. The most potent combination was moved forward into NHPs, which were immunized with clusters of gp160 DNAs (14 different Envs in total) at weeks 0, 4, 8, 12 and boosted at weeks 48 and 85. The vaccine induced cross-clade cellular and humoral responses after two immunizations. These responses increased after each immunization and were maintained into memory. In addition to binding, vaccination also induced tier 1 neutralization. Boosting at week 48 and 85 further increased both responses. We show that DNA plasmids encoding consensus and TF Envs are expressed and induce a potent immune responses. We observed for the first time that exposure of the immune system to multiple Envs at one time can dramatically change the immune phenotype by inducing broader breadth of response which has significant implications for HIV vaccine development.
Percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP) for malignant obstructive jaundice (OJ) in advanced digestive cancers.
Authors: E. Iruarrizaga, E. Azkona, M. Martinez, E. Iza, G. Lopez-Vivanco, A. Munoz Llarena, J. Ferreiro, D. Ballesteros, R. Fernandez, I. Rubio
Journal: Journal of Clinical Oncology (2011)

348 Background: OJ is a relatively frequent complication in patients with advanced malignancies that usually causes refractory symptoms and can make chemotherapy (CT) treatment difficult. In the last years, the use of different non-surgical techniques, such as PTBD or ERCP, is increasing. Methods: From Sep-05 to Aug-10, patients with OJ due to advanced digestive cancers who underwent ERCP or PTBD were included. Baseline characteristics, acute and late complications and outcome were retrospectively collected. Jaundice resolution was recognized if bilirubin value decreased to at least grade 1, after the procedure. Overall survival (OS) was calculated from the date of the technique to the date of death or last follow-up. Results: Seventy-six consecutive patients were collected. Male/Female: 52p/24p; Mean age 63.5 y-o (range: 33-85); ECOG performance status 0/1/2/3: 1/37/27/11; Primary tumour: pancreas 30, biliary tract 18, colorectal 16, gastric 7, and gall bladder 5, and of them, 13% were unresectable locally advanced and 87% metastatic. ERCP was used in 59% of the patients and PTBD in 49% and the proportion of intrahepatic and extrahepatic causes were 1:1. Mean hospital stay was 11.3 days (95% CI 1-21). Twenty- six patients (32%) suffered a complication during the hospital stay: 9 cholangitis, 7 catheter obstruction, 2 bleeding, 2 acute pancreatitis and 6 other, and 8 died of procedure-related adverse event. After hospital discharge there were 34% infections, 17% catheter obstruction and 8% other. After the technique OJ was solved (bilirubin nadir) in 49% of the patients and 55% underwent palliative CT. Median OS was 30 weeks (95% CI: 17-42). Conclusions: PTBD and ERCP are appropriate techniques in patients with malignant OJ and can resolve an absolute contraindication for palliative CT. However, major complications are frequent and a relatively high mortality rate should be expected. Therefore an adequate patient selection is crucial to prevent adverse events. No significant financial relationships to disclose.
Novel Evidence That the Small Chemokine Macrophage Migration Inhibitory Factor (MIF) Is Highly Secreted by Human Rhabdomyosarcomas, Activates Both SDF-1–binding Receptors, CXCR4 and CXCR7, and Unexpectedly Inhibits Recruitment of Stromal Cells to the Growing Tumor.
Authors: Maciej Tarnowski, Rui Liu, Joanna Tarnowska, Janina Ratajczak, Robert Mitchell, Mariusz Z Ratajczak, Magdalena Kucia
Journal: Blood (2010)
P199 A multidisciplinary copd hyperinflation service: report of decision outcomes
Authors: J Chew, J Herre, S Perrott, A Coonar, J Babar, M Scarci, J Parmar, R Mahadeva
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Lung volume reduction (LVR) via unilateral VATS or endoscopic placement of endobronchial valves (EBV) in carefully selected individuals with severe emphysema can result in a major improvement in quality of life. Despite being approved by NICE, there remains patchy service provision across the UK.<sup>1</sup> In 2010, we established a multidisciplinary COPD Hyperinflation service for our region. There is a scarcity of information on such services and we report on our referral outcomes for 2015. <h3>Methods</h3> Our Hyperinflation MDT includes specialist COPD physician, specialist nurse, thoracic radiologist, thoracic surgeon, interventional pulmonologist and transplant physician. We review clinical features, CT and lung function to decide on specialist assessment, progressing to detailed physiological assessment, lung perfusion scanning and MDT discussion in some. We retrospectively reviewed outcomes on 120 patients referred for LVR assessment between 1/1/15–31/12/15. <h3>Results</h3> 111 patients underwent specialist assessment. 20% of patients were discharged, as they did not meet NICE criteria. Nonetheless, many of these patients benefited from clinical phenotyping and management recommendations. 67% of patients were discussed at MDT. 35% of patients were not offered LVR (high risk and lack of hyperinflation targets). 64% of patients were deemed suitable for LVR or transplantation [(EBV or LVRS 37%; LVRS 35%; EBV 15%; EBV bridging to transplantation 7%; transplant 4% (Figure 1)]. One patient received endobronchial coils as part of a clinical study. Patients who are considered suitable for EBV with intact or &lt;10% defect in fissure undergo bronchoscopic balloon catheter assessment for collateral ventilation. <h3>Conclusion</h3> Our experience with this service model shows that LVR can be incorporated into existing pathways. Our model has evolved to triage patients at various points to ensure high quality discussion of selected patients at the dedicated MDT. As a result, the proportion of patients at the MDT offered LVR procedures is relatively high. MDT expertise allows optimal patient selection with effective utilisation of existing resources. We hope that these data will stimulate others to develop local models of care to enable better access to LVR for COPD patients. <h3>Reference</h3> McNulty W, <i>et al</i>. <i>BMJ Open Respirat Res</i> 2014;<b>1</b>:e000023.
CARDIAC ALLOGRAFT SINUS TACHYCARDIA IS ASSOCIATED WITH IMPAIRED EXERCISE TOLERANCE
Authors: Eugenia Raichlin, Sara Varnado, Adam Burdorf, Ashley Huntsberry, Brian Lowes, Ronald Zolty, Hareeprasad Vongooru, Brook Fenske, Aleem Siddique, Michael Moulton, John Um
Journal: Journal of the American College of Cardiology (2016)
Identification of genomic signatures in African-American and Caucasian-American early-onset breast cancer
Authors: Tyesha Farmer, Carl Bruder, Andra Frost, Jan Dumanski, Theresa Strong
Journal: Cancer Research (2008)

1661  Although the incidence of breast cancer in the U.S. is highest overall in Caucasian-American (CA) women, breast cancer in young women occurs at a higher frequency in African-Americans (AA). AA women present with more aggressive disease and, as a consequence, the mortality rates due to breast cancer in this population are higher than those of their CA counterparts across all age groups. AA tumors are more likely to be hormone receptor negative, have higher nuclear and histological grade, exhibit p53 mutations and present at an advanced stage. Tumors in young AA women are more often characterized as basal ‘triple negative’ breast tumors, the breast cancer subtype most difficult to treat. Many factors have been proposed to contribute to breast cancer disparities in AA women. To begin to understand the genetic component of breast cancer disparities, we are investigating genomic signatures of breast tumors from Alabama women. We hypothesized that the differences in tumor phenotype observed between AA and CA early onset breast tumors correlate with specific patterns of genomic aberrations. Our initial study includes 25 AA and 47 CA patients diagnosed with breast cancer at or below the age of 50. Compared to CA women, AA women were significantly more likely to present with grade 3 tumors and tumors of the basal subtype. Immunohistochemical analysis of expression of the tumor suppressors p53 and p27 showed a trend towards a poor prognostic profile in AA women. Using high resolution, whole genome array comparative genomic hybridization, age and grade matched tumors were analyzed for genomic aberrations. Both CA and AA tumors demonstrated complex genomic profiles. A subset of loci was identified that are differentially altered based on ethnicity. In addition, copy number variations have been identified that discriminate breast tumors based on tumor subtype. These studies may lead to the identification of loci that contribute to the increased incidence and aggressiveness of early onset breast cancer in AA women.
PBI-1402: A Non-Toxic Immunorestorative Small Molecule for the Treatment of Anemia.
Authors: Mouna Lagraoui, Brigitte Grouix, Nathalie Julien, Michel Asselin, Dannyck Gaudreau, François Sarra-Bournet, Marie-Josée Morin, Gorazd Krosl, Denis-Claude Roy, Christopher Penney, Lyne Gagnon
Journal: Blood (2006)
A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated Bulky Stage II or Stage III or IV, Low-Grade B-Cell NHL.
Authors: Raul R. Mena, Neal P. Christiansen, David W. Nyman, Yudhishtra Markan, Naveed M. Chowhan
Journal: Blood (2005)
Abstract 4487: Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms
Authors: Sébastien Fortin, Hanane Moussa, Mathieu Gagné-Boulet, Jacques Lacroix, Marie-France Côté, Denis Velic, Joris Pauty, Jean-Yves Masson
Journal: Cancer Research (2015)

Abstract Our research group has developed a new family of promising anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs). PUB-SOs are based on a genuinely new molecular scaffold and pharmacophore constituted by two key aromatic moieties linked by a sulfonate bridge. PUB-SOs block the cell cycle progression in the S-phase and cause DNA double-strand breaks as confirmed by the phosphorylation of H2AX. In addition, PUB-SOs exemplified by prototypical PUB-SO referred to as SFOM-0046 activate selectively ATR-Chk1 pathway in all cell lines studied while it does not activate the ATM-Chk2 pathway. Using immunofluorescence, cell cycle analysis and cell survival assays, we showed that the combination of the Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) and SFOM-0046 provide a proof-of concept that the cytotoxicity of PUB-SOs can be synergized by relevant anticancer drugs. Accordingly, we hypothesized that PUB-SOs inhibit proteins or enzymes involved in critical DNA repair/replication mechanisms. In such a context, we designed a new structure-activity relationship study to assess the effects of the nature and position of different substituents on the aromatic ring B. More than 50 new PUB-SO derivatives were prepared so far and they exhibit antiproliferative activity on the low micromolar range on HT-1080 fibrosarcoma, HT-29 colon carcinoma, M21 skin melanoma and MCF7 breast carcinoma. They block also the cell cycle progression in the S-phase. These results show that substituents on ring B can be modulated to optimize both the antiproliferative and as well as biopharmaceutical properties. In conclusion, PUB-SOs are easily synthesized, purified and pharmacomodulated, and they are therefore promising new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms through a genuinely innovative molecular scaffold and pharmacophore. Citation Format: Sébastien Fortin, Hanane Moussa, Mathieu Gagné-Boulet, Jacques Lacroix, Marie-France Côté, Denis Velic, Joris Pauty, Jean-Yves Masson. Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms. [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 4487. doi:10.1158/1538-7445.AM2015-4487
A Phase I Evaluation of Low Dose Decitabine Targeting DNA Hypermethylation in Patients with Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin’s Lymphoma (NHL): Dose-Limiting Myelosuppression without Evidence of Hypomethylation
Authors: Kristie A. Blum, Zhongfa Liu, David M. Lucas, Robert Baiocchi, Thomas S. Lin, Don Benson, Steven M. Devine, Jeffrey Jones, Leslie Andritsos, Joseph Flynn, Ping Cheng, Zhiliang Xie, Guido Marcucci, Kenneth K. Chan, Michael R. Grever, John C. Byrd
Journal: Blood (2008)
Human cancer immunopeptidomics for efficient CTL immunotherapy
Authors: Vitaly Kochin, Takayuki Kanaseki, Sho Miyamoto, Daichi Morooka, Keigo Moniwa, Yutaro Ikeuchi, Akari Takaya, Yoshihiko Hirohashi, Toshihiko Torigoe, Noriyuki Sato
Journal: Annals of Oncology (2015)
Immune Cytolytic Activity Stratifies Molecular Subsets of Human Pancreatic Cancer
Authors: David Balli, Andrew J. Rech, Ben Z. Stanger, Robert H. Vonderheide
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Immunotherapy has the potential to improve the dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials, including those with single-agent PD-1 or PD-L1 inhibition, have been disappointing. Our aim was to examine the immune landscape of PDA as it relates to aspects of tumor biology, including neoepitope burden. Experimental Design: We used publicly available expression data from 134 primary resection PDA samples from The Cancer Genome Atlas to stratify patients according to a cytolytic T-cell activity expression index. We correlated cytolytic immune activity with mutational, structural, and neoepitope features of the tumor. Results: Human PDA displays a range of intratumoral cytolytic T-cell activity. PDA tumors with low cytolytic activity exhibited significantly increased copy number alterations, including recurrent amplifications of MYC and NOTCH2 and recurrent deletions and mutations of CDKN2A/B. In sharp contrast to other tumor types, high cytolytic activity in PDA did not correlate with increased mutational burden or neoepitope load (MHC class I and class II). Cytolytic-high tumors exhibited increased expression of multiple immune checkpoint genes compared to cytolytic-low tumors, except for PD-L1 expression, which was uniformly low. Conclusions: These data identify a subset of human PDA with high cytolytic T-cell activity. Rather than being linked to mutation burden or neoepitope load, immune activation indices in PDA were inversely linked to genomic alterations, suggesting that intrinsic oncogenic processes drive immune inactivity in human PDA. Furthermore, these data highlight the potential importance of immune checkpoints other than PD-L1/PD-1 as therapeutic targets in this lethal disease. Clin Cancer Res; 23(12); 3129–38. ©2016 AACR.