tbuckley/cabot-search huggingface dataset:
Immunomodulatory gene expression at the fetomaternal interface and in melanoma: Tolerance meets inflammation.
Authors: S. G. Holtan, D. J. Creedon, A. A. Leontovich, S. Markovic
Journal: Journal of Clinical Oncology (2010)

8580 Background: The capability of melanoma cells to evade an immune response remains a substantial barrier to effective therapy, and current models to globally characterize mechanisms of immune evasion are lacking. We hypothesized that an immunomodulatory gene expression pattern that is beneficial during a physiologic process (pregnancy) could provide a holistic model for studying the immunomodulation of melanoma. Methods: We reviewed the literature regarding gene expression of decidualized endometrium and placenta and selected 79 candidate genes to include in a model based upon their involvement in immune responses, tissue invasion, and angiogenesis. Raw gene expression data were downloaded from the Gene Expression Omnibus. We then used principal components analysis (PCA) to visually compare sample grouping based on expression values of all genes with sample grouping based on expression of our immunomodulatory 79 gene model. Finally, expression of genes in the 79 immunomodulatory gene set was determined in 23 Mayo Clinic patients with metastatic melanoma. Results: The captured variances of PC1,2, and 3 accounted for proportionally more of the total variance within the each dataset when the 79 gene filter was applied. OPN (osteopontin) was the most highly upregulated gene in melanoma compared to benign nevi (77.39 fold in GSE4587 and 20.35 fold for GSE3189, p < 0.001 for both) in the set. Among novel immunomodulatory genes not previously explored in melanoma, PTX3 expression was upregulated (4.41 fold in GSE4587, p = 0.04 and 1.54 fold in GSE3189, p = 0.02). 33 other genes were determined to be of interest based upon expression data. Conclusions: By determining gene expression of pregnancy-associated immunomodulators in melanoma, we have identified 35 genes of interest to assess at the protein level by immunohistochemistry in our tumor microarray. By applying knowledge gained from mechanisms of tolerance during pregnancy, we hope to identify novel targets of immune escape in melanoma. No significant financial relationships to disclose.
Abstract 2177: Rutin enhances the antiproliferative effect of 5-FU and oxaliplatin in colon cancer cells
Authors: Farnoud Nasiri, Gorkem Kismali, Merve Alpay, Funda Kosova, Dilek Ulker Cakir, Tevhide Sel
Journal: Cancer Research (2016)

Abstract Background: Rutin is a strong antioxidant molecule and it has advantageous over other flavonoids due to it is a nontoxic and nonoxidizable molecule. The concept of dual therapy of anti-cancer drugs with natural compounds has become a very promising approach in new strategy to treatment. The aim of this study was to evaluate the antiproliferative and apoptotic effects of rutin flavonoids and its efficacy in enhancing the anticancer effects of 5-FU (5-fluorouracil) and oxaliplatin against colon cancer cells. Material and Methods: Caco-2 human colon cancer cells were treated with rutin and/or anticancer drugs (5-FU and oxaliplatin), cell viability and apoptotic parameters were examined. Cell viability was determined by MTT assay. Apoptotic markers (cleaved caspase 3, cleaved PARP and phosphor-Bad) were determined using specific enzyme-linked immunosorbent assay kits. Caspase-8 and caspase-9 were analyzed by colorimetric activity assay kit. DNA fragmentation was analyzed by agarose gel electrophoresis. Results: The exposure Caco-2 human colon cancer cells to rutin, 5-FU and oxaliplatin resulted growth inhibition in a dose- and time-dependent manner. Cell viability assay shows that rutin inhibiting growth of Caco-2 cells at high concentrations (over 1000 μM). Combination with rutin markedly enhanced 5-FU and oxaliplatin growth inhibiting effects on Caco-2 cells. Results suggested that rutin had significant anticancer abilities; such rutin were capable of causing multifold decreases in the half maximal inhibitory concentration IC50 value of 5-FU and oxaliplatin. This flavonoid increased the levels of proteins associated with apoptotic cell death (phospho-Bad, cleaved caspase 3 and cleaved PARP) alone and combination. The activities of caspase 8 and caspase 9 were stimulated by the combination treatment of rutin and oxaliplatin then alone. DNA fragmentation was observed only on combination treatment. Conclusions: Combined treatment with rutin and anticancer drugs (5-FU and/or oxaliplatin) is more effective than the individual treatments of drugs at inhibiting growth of Caco-2 cells. The use of lower 5-FU and oxaliplatin doses, with similar effects, could be also useful to reduce possible adverse effects of these drugs. However, further studies at molecular level are required to elucidate chemopreventive and chemotherapeutic effects of rutin on colon cancer. Citation Format: Farnoud Nasiri, Gorkem Kismali, Merve Alpay, Funda Kosova, Dilek Ulker Cakir, Tevhide Sel. Rutin enhances the antiproliferative effect of 5-FU and oxaliplatin in colon cancer cells. [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 2177.
Abstract 294: The role of the histone deacetylase HDAC 8 in mediating BRAF/MEK inhibitor metastatic dissemination and resistance
Authors: Michael Emmons, Rashed Rab, Ritin Sharma, John Koomen, Keiran Smalley
Journal: Cancer Research (2016)

Abstract BRAF/MEK inhibitor resistance frequently results in increased phosphorylation of EphA2 at S897, which increases the invasive potential of melanoma cells in a ligand-independent manner. Through use of an unbiased phosphoproteomic screen, we identified HDAC phosphorylation as also being increased following the acquisition of BRAF/MEK inhibitor resistance. Treatment with the pan-HDAC inhibitor LBH 589 inhibited EphA2 phosphorylation at S897 and reduced tumor invasion, indicating a role for HDACs in the regulation of the resistance-associated metastatic phenotype. A comparison of HDAC protein levels in matched BRAF inhibitor sensitive/resistant cell lines showed that HDAC6, HDAC8, and HDAC11 protein levels were more highly expressed in BRAF resistant cell lines with HDAC8 being upregulated in 5 of 6 cell line pairs. shRNA knockdown of HDAC8 in the BRAF/MEK inhibitor resistant cell line WM164RR resulted in a decreased in pEphA2 as well as a decrease in pAKT at S473, which is known to directly bind to and phosphorylate EphA2 at S897. Reduced expression of HDAC8 in WM164RR cells resulted in a decrease in the invasive potential of the resistant phenotype as well as a resensitization of these cells to the BRAF inhibitor vemurafenib. HDAC8 overexpression in drug naïve cells led to increased melanoma cell invasion in a 3D spheroid and a matrigel invasion model. Overexpression of HDAC8 was also found to decrease the level of apoptosis following BRAF inhibitor treatment and was associated with increased number of clones in a colony formation assay. Conversely, knocking down HDAC8 with shRNA led to an increase in vemurafenib-mediated apoptosis. Mechanistically, it was found that HDAC8 overexpression increased the speed of adaptive MAPK signaling following BRAF inhibition and that this in turn limited the expression of pro-apoptotic BIM. Overall, these results indicate a dual role for HDAC8 in mediating BRAF/MEK inhibitor resistance and metastatic dissemination. Increased levels of HDAC8 caused an increase in invasion as well as a decrease in vemurafenib-induced apoptosis in BRAF inhibitor sensitive cell lines. Our studies suggest that selective HDAC8 inhibition may be one strategy to limit adaptation to both BRAF and BRAF/MEK inhibitor therapy. Citation Format: Michael Emmons, Rashed Rab, Ritin Sharma, John Koomen, Keiran Smalley. The role of the histone deacetylase HDAC 8 in mediating BRAF/MEK inhibitor metastatic dissemination and resistance. [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 294.
Blood pressure variability and cardiovascular disease: systematic review and meta-analysis
Authors: Sarah L Stevens, Sally Wood, Constantinos Koshiaris, Kathryn Law, Paul Glasziou, Richard J Stevens, Richard J McManus
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood pressure, with cardiovascular disease events and mortality. <b>Data sources</b>&nbsp;Medline, Embase, Cinahl, and Web of Science, searched to 15 February 2016 for full text articles in English. <b>Eligibility criteria for study selection</b>&nbsp;Prospective cohort studies or clinical trials in adults, except those in patients receiving haemodialysis, where the condition may directly impact blood pressure variability. Standardised hazard ratios were extracted and, if there was little risk of confounding, combined using random effects meta-analysis in main analyses. Outcomes included all cause and cardiovascular disease mortality and cardiovascular disease events. Measures of variability included standard deviation, coefficient of variation, variation independent of mean, and average real variability, but not night dipping or day-night variation. <b>Results</b>&nbsp;41 papers representing 19 observational cohort studies and 17 clinical trial cohorts, comprising 46 separate analyses were identified. Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively). <b>Conclusions</b>&nbsp;Long term variability in blood pressure is associated with cardiovascular and mortality outcomes, over and above the effect of mean blood pressure. Associations are similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short term variability showed similar associations. Future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date. <b>Systematic review registration</b>&nbsp;PROSPERO CRD42014015695.
Comment on “Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice”
Authors: Emanuela Guerra, Mauro Piantelli, Saverio Alberti
Journal: Science Translational Medicine (2016)

A report that low doses of resveratrol can suppress intestinal adenoma in a mouse model appears confounded because in a slightly different protocol, resveratrol has the opposite effect.
Pentraxin 3 deletion aggravates allergic inflammation through a T H 17-dominant phenotype and enhanced CD4 T-cell survival
Authors: Jyoti Balhara, Lianyu Shan, Jingbo Zhang, Anik Muhuri, Andrew J. Halayko, Muhamad S. Almiski, Diana Doeing, John McConville, Martin M. Matzuk, Abdelilah S. Gounni
Journal: Journal of Allergy and Clinical Immunology (2016)

Pentraxin 3 (PTX3) is a multifunctional molecule that plays a nonredundant role at the crossroads between pathogen clearance, innate immune system, matrix deposition, female fertility, and vascular biology. It is produced at sites of infection and inflammation by both structural and inflammatory cells. However, its role in allergen-induced inflammation remains to be tested.We sought to determine the effect of Ptx3 deletion on ovalbumin (OVA)-induced allergic inflammation in a murine model of asthma.Bronchoalveolar lavage fluid was collected from patients with severe asthma and healthy subjects, and the level of PTX3 was determined by using ELISA. Ptx3+/+ and Ptx3-/- mice were sensitized and challenged with OVA and bronchoalveolar lavage fluid, and the lungs were collected for assessing inflammation. Lung tissue inflammation and mucus production were assessed by means of flow cytometry and hematoxylin and eosin and periodic acid-Schiff staining, respectively. flexiVent was used to determine airway resistance to methacholine in these mice.Here we report that mice with severe asthma and OVA-sensitized/challenged mice had increased PTX3 levels in the lungs compared with healthy control mice. Mice lacking PTX3 have exaggerated neutrophilic/eosinophilic lung inflammation, mucus production, and airway hyperresponsiveness in an experimental model of OVA-induced asthma. Furthermore, OVA-exposed lung Ptx3-/- CD4 T cells exhibit an increased production of IL-17A, an effect that is accompanied by an increased signal transducer and activator of transcription 3 phosphorylation, reduced IL-2 production, and enhanced activation and survival. Also, we observed an increase in numbers of IL-6- and IL-23-producing dendritic cells in OVA-exposed Ptx3-/- mice compared with those in wild-type control mice.Altogether, PTX3 deficiency results in augmented airway hyperresponsiveness, mucus production, and IL-17A-dominant pulmonary inflammation, suggesting a regulatory role of PTX3 in the development of allergic inflammation.
Abstract 4067: Cell phone use is associated with an inflammatory cytokine profile of parotid gland saliva
Authors: Ricardo S. Gomez, Elisa C. Siqueira, Fabrício Tinôco A. Souza, Efigênia F. Ferreira, Renan P. Souza, Eitan Friedman, Marcus V. Gomez, Carolina C. Gomes
Journal: Cancer Research (2016)

Abstract There is controversy on the effects of the non-ionizing radiation emitted by cell phones on cellular processes and the impact of such radiation exposure on health. Conflicting results were reported on the association between cell phone use and parotid tumor development. Chronic inflammation is associated with an increased risk for cancer, such as seen in ulcerative colitis. To evaluate the effect that cell phone use has on the parotid gland, cytokine expression profile was determined in the saliva produced by the parotid glands in healthy volunteers, and correlated with self-reported cell phone use and laterality. The following parameters were determined, in 83 Brazilian individuals in saliva produced by the parotid glands comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to that from the contralateral parotid: salivary flow, total protein concentration, IL-1β, IL-6, IL-10, IFN-γ and TNF-α by ELISA. After multiple testing correction, decreased IL-10 and increased IL-1β salivary levels in the ipsilateral side compared with the contralateral side (p&amp;lt;0.05) were detected. Subjects who used cell phones for more than 10 years presented higher differences between IL-10 levels in ipsilateral versus contralateral parotids (p = 0.0012). No difference was observed in any of the tested parameters in correlation with cell phone monthly usage in minutes. We conclude that exposure of parotid glands to cell phones can alter salivary IL-10 and IL-1β levels. These findings suggest a pro-inflammatory profile on parotid naturally exposed to cell phones, which can be associated not only to the radiation emitted by the device but with the warming caused by radiation and the battery of the cell during use. Supported by: FAPEMIG (Fundação de Amparo à Pesquisa de Minas Gerais), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Brazil Citation Format: Ricardo S. Gomez, Elisa C. Siqueira, Fabrício Tinôco A. Souza, Efigênia F. Ferreira, Renan P. Souza, Eitan Friedman, Marcus V. Gomez, Carolina C. Gomes. Cell phone use is associated with an inflammatory cytokine profile of parotid gland saliva. [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 4067.
PTH-076 Radiation exposure in crohn’s-a comparison between a teaching hospital and a dgh and the impact of new technologies in imaging: Abstract PTH-076 Table 1
Authors: S Savva
Journal: Gut (2015)

<h3>Introduction</h3> In 2012 we audited Crohn’s patients’ exposure to radiation in the first year of diagnosis at the Leicester Royal Infirmary (LRI) and compared this to patients diagnosed prior to the introduction of small bowel ultrasound scanning (and more widespread use of MRI) in our department. We had hoped to find that over that time (10 years) exposure to radiation had fallen, but unfortunately the data actually showed a 47% increase in exposure over that time. With this in mind we decided to repeat the audit in Kettering General Hospital, a DGH without small bowel US or easy access to MRI scanning. <h3>Method</h3> Using a key word search of clinic letters we identified 79 patients diagnosed with Crohn’s disease between 1999 and 2014, and looked at their exposure to ionising radiation in their first year of diagnosis (6 months prior to 6 months post diagnosis). <h3>Results</h3> Interestingly we once again identified a rise in average exposure to radiation, this time by 54%. Comparing this to the 47% increase we identified at the LRI we are convinced that this is a real phenomenon. In the LRI we found that much of the rise was attributable to Computerised Tomography (CT) scanning, with a huge surge in its use – data that we have replicated in this audit in a DGH, where we have demonstrated a 3-fold increase. The notable difference is that the use of newer modalities (US and MRI) in this DGH has not changed greatly over time in comparison to the teaching hospital where we observed a huge surge in the use of these. We believe that this is the reason for the relatively slower rise in the overall exposure to radiation in the teaching hospital (around 7%). <h3>Conclusion</h3> We have now looked at Crohn’s patients’ exposure to radiation over 15 years in two different settings and the results are clear- there is a huge increase in the exposure of such patients to potentially harmful ionising radiation, and we think this data could be replicated throughout the country. Most of the increase is clearly attributable to CT scanning, and we think this may be due to its increased availability and lower cost. We also believe increasingly defensive practice by clinicians may be playing a role, and this might be evidenced by the fact that we found a doubling of the number of plain abdominal films performed in both hospitals. Although our results are cause for concern we believe that with recognition of the problem practice can be changed to try and protect these patients. We also hope that the development of new modalities such as low-dose computerised tomography will impact this risk positively. <h3>Disclosure of interest</h3> None Declared.
Intratumoral pharmacokinetics determined with microdialysis in a patient with glioblastoma multiforme following systemic administration of high dose methotrexate
Authors: J. J. Olson, J. Supko, S. Phuphanich, E. McKenzie, S. A. Grossman
Journal: Journal of Clinical Oncology (2005)

1569 Background: The delivery of therapeutic concentrations of chemotherapeutic agents to brain tumors remains a major concern in the design and interpretation of clinical brain tumor trials. Methods: This study was approved by the National Cancer Institute and IRB at each participating site. Patients with recurrent and refractory glioblastoma multiforme (GBM) where biopsy or partial resection followed by high dose methotrexate (MTX) were planned were eligible. At surgery a microdialysis catheter was placed within residual contrast enhancing tumor. Modified Ringer’s solution was delivered to the catheter at 1 μl/min. On the following day, 12 grams/m2 of intravenous MTX (adjusted for renal function) were administered over 4 hours. Plasma and microdialysate were collected at 30 minute intervals. MTX was assayed using high performance liquid chromatography with mass spectrometric detection (0.5 ng/ml lower limit of quantitation). Results: The first patient evaluated was a 51 year old who had a biopsy to confirm tumor progression after prior surgery, radiation, Gliadel, and temozolomide. The plasma pharmacokinetics of MTX behaved as expected. Renal function remained unchanged and the leukovorin rescue was administered as per protocol. MTX concentrations in extracellular fluid within the GBM rose rapidly to a maximum of 57 μM and subsequently decayed in a monoexponential manner with a half-life of 12.3 h. MTX concentrations in the dialysate exceeded plasma levels 16 hours after the MTX infusion ended. The patient subsequently developed urosepsis with neutropenia, but no mucositis or diarrhea, and died 3 weeks later after care was withdrawn. Detailed review by NABTT, CTEP, and the study site found no association with the microdialysis catheter and an uncertain relationship to MTX. Conclusions: This is the first reported use of microdialysis in a human to monitor local concentrations of a systemically administered anticancer drug within a brain tumor. This approach could significantly impact the selection of drugs, dosing schedules, and routes of administration for future brain tumor trials. No significant financial relationships to disclose.
The Systemic Effects of Vorinostat in Patients (Pts) with Cutaneous T-Cell Lymphoma (CTCL): Post-Hoc Analyses in Pts with High Blood Tumor Burden.
Authors: Madeleine Duvic, Youn H Kim, Timothy M Kuzel, Theresa R Pacheco, Francine M Foss, Sareeta Parker, Syed Rizvi, Cong Chen, Jean Marie Arduino, Elise A. Olsen
Journal: Blood (2009)