tbuckley/cabot-search huggingface dataset:
Abstract 4092: High mast cell density is associated with improved prognosis in colon cancer patients
Authors: Anita Sjölander.
Journal: Cancer Research (2016)

Abstract Background. Inflammatory cells and inflammatory mediators play an important role in colon cancer. However, the role of mast cells (MCs) in colon cancer progression remains unclear. Pro-inflammatory cysteinyl leukotrienes (CysLTs) have been associated with colorectal cancer (CRC) development. In particular, previous studies have shown that CRC patients with increased expression of cysteinyl leukotriene receptor 1 (CysLTR1) have poorer prognoses, and Cysltr1−/− mice display fewer intestinal polyps. The aim of the present study was to investigate the clinical and prognostic significance of mast cell density (MCD) in patients with CRC and to determine the significance of CysLTR1 on MCD in a mouse model of colitis-associated colon cancer (CAC). Materials and methods. A tissue microarray (TMA) of primary colon cancers from 72 patients was stained with MC anti-tryptase and anti-chymase antibodies. Mouse colon tissue was stained with MC anti-tryptase antibody. Immunohistochemistry was used to identify MCD in cancerous and normal areas of patient tissues and in polyp/tumour, adjacent and normal areas of mouse tissues. Results. In patient samples, the mean MCD was significantly higher in normal tissue than in cancer tissue (p = 0.0009). Patients with a high MCD in cancer tissue showed better overall survival compared with those with a low MCD (hazard ratio (HR) 0.575; 95% confidence interval (CI), 0.293 - 1.130). The same result was observed in patients aged 55-75 years (HR 0.332; 95% CI 0.121 - 0.911) and among patients without distant metastasis at diagnosis (HR 0.311; 95% CI 0.118 - 0.821). In the CAC mouse model, Cysltr1−/− mice had fewer intestinal polyps and significantly higher MCD in polyp/tumour areas compared with controls. Conclusion. A high MCD in cancer tissue correlates with longer patient survival. In Cysltr1−/− CAC mice, a high polyp/tumour MCD also appears beneficial. Thus, these results indicate that a high MCD is a good prognostic factor. Citation Format: Anita Sjölander. High mast cell density is associated with improved prognosis in colon cancer patients. [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 4092.
Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1–mutated common variable immunodeficiency disease
Authors: Vassilios Lougaris, Daniele Moratto, Manuela Baronio, Giacomo Tampella, Jos W.M. van der Meer, Raffaele Badolato, Manfred Fliegauf, Alessandro Plebani
Journal: Journal of Allergy and Clinical Immunology (2016)
The effect of <i>P53 gene</i> status on the interaction of vorinostat (Suberoylanilide Hydroxamic Acid-SAHA) with carboplatin in non-small cell lung cancer (NSCLC) cell lines
Authors: P. Hershberger, T. K. Owonikoko, S. Ramalingam, C. P. Belani
Journal: Journal of Clinical Oncology (2007)

10567 Background: Vorinostat, a Histone Deacetylase (HDAC) inhibitor is a novel targeted antineoplastic agent with promising activity when combined with carboplatin-paclitaxel against NSCLC. The exact molecular mechanism underlying its growth inhibitory and apoptotic effects is not well understood. We investigated the influence of p53 gene status on the interaction of vorinostat and carboplatin (a DNA targeting agent) in various NSCLC cell lines. Methods: NSCLC cells with wild type p53 (A549, 128.88T), mutant p53 (201T) and p53 null phenotype (Calu-1) were used. Cytotoxicity induced by serial dilution of carboplatin in the presence and absence of a fixed dose (1μM) of vorinostat was assessed by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay. In a separate experiment, cells were also transiently transfected with a p21 promoter-luciferase reporter construct to assess p53 activation following a 24 h exposure to vorinostat, carboplatin, or vorinostat/Carboplatin combination. Luciferase activity was quantified by luminometry and corrected for total protein. Results: Vorinostat displayed single agent activity in each cell line, with greater growth inhibition observed in the p53 mutant and null cells. Synergistic interactions between carboplatin and vorinostat were observed in p53 wild type cells and the IC50 for carboplatin was reduced 3- to 5-fold. In contrast, the interaction between vorinostat and carboplatin was additive or less than additive in p53 mutant and p53 null cells. Vorinostat also increased expression of the p21 reporter construct in each of the cell lines. Conclusions: Vorinostat regulates p21 gene expression and elicits anti-tumor activity in NSCLC cells independent of their p53 status. Vorinostat potentiates carboplatin-induced cytotoxicity in NSCLC with wild type p53 but not p53 deficient cells, suggesting involvement of a p53 dependent pathway. The addition of vorinostat may allow for a reduction in standard dose of carboplatin with improvement in overall therapeutic index. A phase II/III clinical trial is in progress to evaluate vorinostat in combination with carboplatin-based regimen in advanced NSCLC. Support: CA099168–01, ASCO Foundation CDA No significant financial relationships to disclose.
Abstract 1829: The validation of a pyrosequencing KRAS mutation detection assay
Authors: Matthew L. Poulin, Ann Meyer, E. Andrew Mead, Jessica Xu, Ryan Drennan, Liyin Yan
Journal: Cancer Research (2016)

Abstract Mutations in the KRAS gene, especially affecting the codon 12 and 13 region of the Kras protein, have implications in the treatment of certain cancer types. Because of the current potential for the FDA to oversee laboratory developed procedures (LPDs), it is imminently important that the validation of such tests be published to ensure that it is shown that these LPDs are properly reviewed and properly tested within the CLIA guidelines, thus keeping LPDs within the CLIA regulatory domain. We have developed a pyrosequencing assay that can detect eleven mutations in the codon 12 and 13 position of the KRAS gene. Our validation consisted of a sensitivity study in which a purified mutant PCR product was introduced into a wildtype DNA background and diluted down to undetectable levels. This sensitivity test was done on six different KRAS codon 12/13 mutants to determine the detection limit of the assay. Intra- and inter-assay precision and assay accuracy was determined by comparing assay results of over 40 total samples, both mutant and wild type, over five days carried out by two technicians. The results will show that this KRAS pyrosequencing assay falls within the acceptance criteria for sensitivity, accuracy and precision. Citation Format: Matthew L. Poulin, Ann Meyer, E. Andrew Mead, Jessica Xu, Ryan Drennan, Liyin Yan. The validation of a pyrosequencing KRAS mutation detection assay. [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 1829.
PTU-057 Split liver transplant recipients are less likely to require peri-operative renal replacement therapy than full-size liver transplant controls: Abstract PTU-057 Table 1
Authors: J A Leithead, M J Armstrong, C Corbett, M Andrew, C Kothari, F Tinti, B K Gunson, D Mirza, P Muiesan, J W Ferguson
Journal: Gut (2012)

<h3>Introduction</h3> Several small studies have suggested that split liver transplant (SLT) recipients have an increased frequency of peri-operative acute kidney injury (AKI). However, given that hepatic ischaemia-reperfusion injury may play a role in the pathogenesis of peri-transplant AKI, the optimal donor selection of split liver transplantation could have a favourable impact on renal outcomes. Our aim was to compare renal outcomes in SLT recipients with matched full-size liver transplant (FSLT) controls. <h3>Methods</h3> Single-centre study of 72 patients who received a SLT for chronic liver disease 01/2007–06/2011. 72 FSLT (Donation after Brain Death) controls were matched by propensity-risk-score. Definitions: AKI, peak creatinine ≥2 times baseline; chronic kidney disease (CKD), MDRD4 eGFR &lt;60 ml/min/1.73 m<sup>2</sup>. <h3>Results</h3> SLT recipients and FSLT controls were well matched on confounders. Split liver grafts had a younger donor age (p&lt;0.001), longer cold ischaemic time (p=0.026) but similar warm ischaemic time (p=0.213). There was no difference in the intra-operative red cell concentrate requirements between the groups (p=0.460). During the immediate post-operative period, the median peak AST was 1156 U/L for SLT recipients and 1124 U/L for FSLT controls (p=0.960). The frequency of re-laparotomy for bleeding (p=0.310), primary non-function (p=1.000), sepsis (p=0.643) and biliary complications were comparable (p=1.000). Estimated 3-year patient survival was 90.0% and 91.8% for SLT recipients and controls, respectively (log-rank p=0.400). Peri-operative and long-term renal outcomes are outlined in Abstract PTU-057 table 1. There was no difference between the two groups, with the exception of renal replacement therapy; SLT recipients were less likely to require peri-operative renal replacement therapy than FSLT controls (p=0.048). <h3>Conclusion</h3> SLT recipients are less likely to require peri-operative renal replacement therapy than well matched FSLT recipients. Higher graft quality and/or smaller graft volume may have a beneficial renal-sparing effect. <h3>Competing interests</h3> None declared.
The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer occurrence: A population-based study
Authors: M. Schaapveld, P. H. B. Willemse, E. G. E. de Vries, W. T. A. van der Graaf, O. Visser, M. J. Louwman, R. Otter, J. W. W. Coebergh, F. E. van Leeuwen
Journal: Journal of Clinical Oncology (2005)

518 Purpose: To evaluate the impact of age and adjuvant therapy on contralateral invasive breast cancer (CBC) risk and the prognostic significance of CBC. Patients and Methods: The study included 33,930 surgically treated stage I-IIIA breast cancer patients diagnosed in the Netherlands between 1988–2000. The prognostic impact of CBC was studied in a time-dependent Cox model. Results: With a median follow-up of 5.3 years, 476 CBC were diagnosed <6 months after the index cancer (synchronous) and 999 thereafter (metachronous). Older age and lobular histology increased synchronous CBC risk. The Standardized Incidence Ratio (SIR) of any CBC was 2.9 (95% Confidence Interval (95%CI) 2.7–3.1). The SIR of metachronous CBC decreased with age, from 13.4 (95%CI 9.6–18.2) for women <35 to 1.6 (95%CI 1.4–1.8) for women ≥60 years. The absolute excess risk of metachronous CBC was 29.9/10,000 person-years. The cumulative risk of metachronous CBC increased with about 0.5%/year, reaching 5.3% after 10 years. Adjuvant hormonal (Hazard ratio (HR) 0.54; 95%CI 0.44–0.68) and chemotherapy (HR 0.67; 95%CI 0.51–0.87) markedly decreased metachronous CBC risk. Radiotherapy was associated with a 60% increased CBC risk (95%CI 1.04–2.62) among patients <40 years. Adjusted for age and stage of the index cancer, the survival of patients with metachronous CBC was worse than for unilateral breast cancer patients (HR 1.47; 95%CI 1.33–1.63). Conclusion: Young breast cancer patients experience very high synchronous and metachronous CBC risk. Adjuvant hormonal or chemotherapy considerably reduced the risk of CBC. The occurrence of CBC adversely affects prognosis, emphasizing the necessity of long-term surveillance directed at early CBC-detection. No significant financial relationships to disclose.
E2f8 mediates tumor suppression in postnatal liver development
Authors: Lindsey N. Kent, Jessica B. Rakijas, Shusil K. Pandit, Bart Westendorp, Hui-Zi Chen, Justin T. Huntington, Xing Tang, Sooin Bae, Arunima Srivastava, Shantibhusan Senapati, Christopher Koivisto, Chelsea K. Martin, Maria C. Cuitino, Miguel Perez, Julian M. Clouse, Veda Chokshi, Neelam Shinde, Raleigh Kladney, Daokun Sun, Antonio Perez-Castro, Ramadhan B. Matondo, Sathidpak Nantasanti, Michal Mokry, Kun Huang, Raghu Machiraju, Soledad Fernandez, Thomas J. Rosol, Vincenzo Coppola, Kamal S. Pohar, James M. Pipas, Carl R. Schmidt, Alain de Bruin, Gustavo Leone
Journal: Journal of Clinical Investigation (2016)

E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.
Belatacept and Long-Term Outcomes in Kidney Transplantation
Authors: Leonardo V Riella, Steven Gabardi, Jamil Azzi
Journal: New England Journal of Medicine (2016)

To the Editor: Vincenti and colleagues (Jan.28 issue) 1 found that the risk of death or graft loss was lower with belatacept-based immunosuppression than with a cyclosporine-based regimen among kidney-transplant recipients during 7 years of follow-up.The results are notable, because data on long-term clinical outcomes are rare in the field.However, no data on the dosing of mycophenolate mofetil through the follow-up period were provided, which raises concern about the interpretation of the results.According to the trial protocol, patients initiated mycophenolate mofetil at a dose of 2 g per day, with dose adjustments at the investigator's discretion.Exposure to mycophenolic acid, the active immunosuppressant, is the best metric for the efficacy of mycophenolate mofetil. 2,3Cyclosporine inhibits enterohepatic recirculation of mycophenolic acid, thereby reducing exposure by 30 to 40%. 2-5Thus, even if the patients assigned to belatacept and those assigned to cyclosporine received similar doses of myco-phenolate mofetil, the former may have been exposed to a substantially higher amount of active immunosuppressant.Because mycophenolate mofetil inhibits the proliferation of T and B lymphocytes, higher exposure in the belatacept-treated patients could account for the lower risk of death or graft loss through a reduction in donor-specific antibodies or other exposure-dependent mechanisms.Mycophenolate dosing and the exposure metrics over time are needed to compare the intervention and control groups properly.
Chromatic Multifocal Pupillometer for Objective Perimetry and Diagnosis of Patients with Retinitis Pigmentosa
Authors: Ron Chibel, Ifat Sher, Daniel Ben Ner, Mohamad O. Mhajna, Asaf Achiron, Soad Hajyahia, Alon Skaat, Yakir Berchenko, Bernice Oberman, Ofra Kalter-Leibovici, Laurence Freedman, Ygal Rotenstreich
Journal: Ophthalmology (2016)
Abstract 3292: Manipulating osteoblast differentiation in order to inhibit protection of AML cells within the bone marrow
Authors: Rosalie Sterner, Kimberly Kremer, Amel Dudakovic, Scott Kaufmann, Jennifer Westendorf, Andre van Wijnen, Karen Hedin
Journal: Cancer Research (2016)

Abstract While standard chemotherapeutics can initially induce remission in patients with acute myelogenous leukemia (AML), patients often relapse in part due to the protective bone marrow microenvironment, which promotes the survival of AML cells. Using an in vitro cell culture model of the bone marrow, our lab recently showed that differentiating osteoblasts potently protect AML cells from apoptosis. In addition, we found that differentiating osteoblasts treated with histone deacetylase inhibitors (HDACi) fail to protect AML cells in this model. Since HDACi decreased the expression of genes required for osteoblast differentiation, we hypothesize that blocking specific stage(s) of osteoblast differentiation may make AML cells within the bone marrow more susceptible to chemotherapy. We are currently disrupting specific osteoblast differentiation stages via molecular or therapeutic drug manipulation and exploring the impact on AML cell survival both in cell culture models of the bone marrow microenvironment and in a mouse model of AML. The results of our studies will characterize novel bone marrow molecular and cellular interactions that promote the survival of AML cells. Targeting these interactions in combination therapies may more completely eradicate the AML cell reservoir and better prevent relapse. Citation Format: Rosalie Sterner, Kimberly Kremer, Amel Dudakovic, Scott Kaufmann, Jennifer Westendorf, Andre van Wijnen, Karen Hedin. Manipulating osteoblast differentiation in order to inhibit protection of AML cells within the bone marrow. [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 3292.
Delivery of peri-operative chemotherapy for muscle-invasive bladder cancer (MIBC) in routine clinical practice: Does regimen and timing matter?
Authors: Christopher M. Booth, D. Robert Siemens, Yingwei Peng, Ian Tannock, William J. Mackillop
Journal: Journal of Clinical Oncology (2014)

4537 Background: Few studies have documented regimens used and timing of peri-operative chemotherapy for MIBC in routine practice. In metastatic bladder cancer cisplatin has superior efficacy to carboplatin. Time to initiation of adjuvant chemotherapy (TTAC) from surgery is known to be associated with survival in other solid tumors. Here we describe regimens used and TTAC in the general population of Ontario, Canada. Methods: Treatment and physician billing records were linked to the Ontario Cancer Registry to describe use of neoadjuvant (NACT) and adjuvant (ACT) chemotherapy among all patients with MIBC treated with cystectomy in Ontario 1994-2008. Time to initiation of ACT (TTAC) was measured from cystectomy. Multivariate Cox regression was used to identify factors associated with overall (OS) and cancer-specific survival (CSS). Results: Of 2944 patients undergoing cystectomy, 4% (129/2944) and 19% (571/2944) were treated with NACT and ACT respectively. Five-year OS was 25% (95%CI 17-34%) for NACT, 29% (95%CI 25-33%) for ACT cases. Among patients with identifiable drug regimens, cisplatin was used in 82% (253/308) and carboplatin in 14% (43/308). The most common regimens were gemcitabine-cisplatin (54%, 166/308) and MVAC (21%, 66/308). Mean TTAC was 10 weeks; 23% of patients had TTAC >12 weeks. Advanced age (70+ years OR 3.86, 95%CI 1.25-11.9) and lower socioeconomic status (poorest quintile OR 2.38, 95%CI 1.13-5.02) were more likely to have TTAC > 12 weeks. Patients with node positive disease were less likely to have TTAC >12 compared to node negative (OR 0.58, 95%CI 0.34-0.99). TTAC greater than 12 weeks was associated with inferior OS (HR 1.28, 95%CI 1.00-1.62) and CSS (HR 1.30, 95%CI 1.00-1.69). In adjusted analyses, OS and CSS were lower among patients treated with carboplatin compared to those treated with cisplatin; OS HR 2.14 (95%CI 1.40-3.29) and CSS HR 2.06 (95% CI 1.26-3.37). Conclusions: Most patients with MIBC in the general population receive cisplatin and this may be associated with superior outcomes to carboplatin. Initiation of ACT beyond 12 weeks is associated with inferior survival. Patients should start ACT as soon as they are medically fit to do so.
Abstract 3138: The Effect of Interactions among Variants of CD36 on Hypertensive Heart Disease Phenotypes
Authors: Lisa de las Fuentes, C. Charles Gu, Alan D Waggoner, Jyh Ming Juang, Victor G Davila-Roman
Journal: Circulation (2008)

Alterations in myocardial metabolism are implicated in mediating hypertensive heart disease (HHD). We hypothesize that variants in CD36 modulate HHD phenotypes both individually and collectively via interactions among CD36 variants and with those in other metabolic regulatory genes. Cardiovascular (CV) phenotypes were characterized by echocardiography and carotid artery ultrasonography. The association between race-specific CD36 tagSNPs (r 2 &gt;0.8) and HHD traits were tested in Caucasian (C, n=608) and African-American (AA, n=228) adults. Association between dependent variables and individual SNPs were tested by regression analysis adjusting for known confounding covariates. Tests for interaction were carried out by first examining within-gene cis -interactions by regression against haplotypes in CD36, followed by exploratory analysis of cross-gene interactions between CD36 and PPARα, PPARγ, and PGC1α using Bayesian network (BNT) analyses. A total of 14 and 52 CD36 SNPs in C and AA, respectively, were evaluated. In C, no significant main effects for individual CD36 SNPs were detected while 3 CD36 haplotypes were associated with LV diastolic function, LV mass, and LV ejection fraction suggesting a role for interaction of cis -acting elements. In AA, 15 individual SNPs and 17 CD36 haplotypes were associated with HHD-related traits. Exploratory BNT analyses including significant haplotypes from the 4 genes identified meaningful gene-gene interactions in both races, highlighting the complex nature of interactions among CD36 and metabolic regulatory genes in the etiology that deserves further investigation. Figure. BNT of all significant (p=0.05) haplotypes from CD36, PGC1α, PPARα, PPARγ in the African-American cohort. Dependent variable (LVM/HI 27 ) and body mass index (potential covariate) shown in orange.