tbuckley/cabot-search huggingface dataset:
Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses
Authors: Ans De Beuckelaer, Charlotte Pollard, Sandra Van Lint, Kenny Roose, Lien Van Hoecke, Thomas Naessens, Vimal Kumar Udhayakumar, Muriel Smet, Niek Sanders, Stefan Lienenklaus, Xavier Saelens, Siegfried Weiss, Guido Vanham, Johan Grooten, Stefaan De Koker
Journal: Molecular Therapy (2016)

Given their high potential to evoke cytolytic T cell responses, tumor antigen-encoding messenger RNA (mRNA) vaccines are now being intensively explored as therapeutic cancer vaccines. mRNA vaccines clearly benefit from wrapping the mRNA into nano-sized carriers such as lipoplexes that protect the mRNA from degradation and increase its uptake by dendritic cells in vivo. Nevertheless, the early innate host factors that regulate the induction of cytolytic T cells to mRNA lipoplex vaccines have remained unresolved. Here, we demonstrate that mRNA lipoplexes induce a potent type I interferon (IFN) response upon subcutaneous, intradermal and intranodal injection. Regardless of the route of immunization applied, these type I IFNs interfered with the generation of potent cytolytic T cell responses. Most importantly, blocking type I IFN signaling at the site of immunization through the use of an IFNAR blocking antibody greatly enhanced the prophylactic and therapeutic antitumor efficacy of mRNA lipoplexes in the highly aggressive B16 melanoma model. As type I IFN induction appears to be inherent to the mRNA itself rather than to unique properties of the mRNA lipoplex formulation, preventing type I IFN induction and/or IFNAR signaling at the site of immunization might constitute a widely applicable strategy to improve the potency of mRNA vaccination.
Abstract 442: RASSF1A gene promoter methylation in primary tumors, adjacent morphologically normal tissues and plasma samples of patients with high grade serous ovarian cancer
Authors: Lydia Giannopoulou, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi S. Lianidou
Journal: Cancer Research (2016)

Abstract Introduction: RASSF1A promoter methylation is frequent in high grade serous ovarian cancer (HGSC), the most common histological subtype. We examined RASSF1A promoter methylation in primary tumors, adjacent normal tissues and corresponding plasma samples of patients with HGSC, using real-time methylation specific PCR (real-time MSP) and methylation-sensitive high-resolution melting analysis (MS-HRMA). Materials and methods: A training group of 78 primary HGSC FFPEs was first analyzed using both real-time MSP and MS-HRMA. Our validation group consisted of 61 primary HGSC FFPEs, 58 adjacent tissues (analyzed using both real-time MSP and MS-HRMA), and 59 corresponding plasma samples (analyzed using real-time MSP). The specificity of both assays was evaluated by analyzing a group of 16 fallopian tube samples from healthy individuals. OVCAR29 and IGROV1 cell lines were used as positive controls. Results: In the training group, RASSF1A promoter methylation was detected in 33/78 (42.3%) by real-time MSP and in 33/78 (42.3%) by MS-HRMA (Agreement = 94.9%, P = 0.001, k = 0.895). The validation group results are shown in Table 1. According to the semi-quantitative MS-HRMA, RASSF1A promoter methylation was detected at significantly lower percentages in the adjacent morphologically normal tissues, compared to the paired primary tumors. In corresponding plasma samples, methylation was detected in 15/59 (25.4%) (Agreement with paired tumors = 60.7%, P = 0.259, k = 0.143). Both real-time MSP and MS-HRMA revealed no RASSF1A promoter methylation in the small group of normal fallopian tubes (n = 16). Conclusion: RASSF1A promoter is highly methylated in primary tumors and at lower percentages in the adjacent normal tissues. In all cases, MS-HRMA gave comparable results with real-time MSP. Evaluation of the clinical significance of RASSF1A promoter methylation in corresponding plasma requires further investigation. Table 1RASSF1A promoter methylationMethodPrimary tumor samples (validation group) N = 61Adjacent tissues N = 58Agreement (paired samples, N = 57)Real time MSP25/61 (41%)17/58 (29.3%)48/57(84.2%), P = 0.001, k = 0.652MS-HRMA28/61 (45.9%)21/58 (36.2%)51/57(89.5%), P = 0.001, k = 0.782Agreement (methods)58/61(95.1%), P = 0.001, Cohen's kappa = 0.90050/58(86.2%),P = 0.001, Cohen's kappa = 0.689 Citation Format: Lydia Giannopoulou, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi S. Lianidou. RASSF1A gene promoter methylation in primary tumors, adjacent morphologically normal tissues and plasma samples of patients with high grade serous ovarian cancer. [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 442.
Abstract LB-043: Improving rectal cancer therapy using a patient-derived tumor xenograft model
Authors: Ernest R. Camp, Cindy Wang, Katie Hurst, Lourdes M. Nogueira, Victoria J. Findlay
Journal: Cancer Research (2016)

Abstract Mechanisms of locally advanced rectal cancer (LARC) neoadjuvant chemoradiation resistance are poorly understood. Current research models to study this issue are incomplete and restricted by the limited supply of untreated tissue samples. Patient-derived xenografts (PDX) are commonly developed from surgical specimens and can serve as effective tools to investigate therapy. We previously demonstrated that the SNAI2/ miR-145 signaling axis enhanced the tumor-initiating cell (TIC) and chemotherapy resistance. We developed a unique PDX model from pre-neoadjuvant therapy LARC biopsy samples to study chemoradiation resistance. Further, we hypothesized that TICs isolated from LARC patient-derived xenografts would demonstrated increased SNAI2/ miR-145 signaling. Methods: Fresh LARC endoscopic biopsy samples were digested using Liberase DH to yield a dissociated single-cell solution. All in vivo experiments consisted of injecting cells with Matrigel subcutaneously into NSG NODSCID/IL2Rgnull immunocompromised mice. Xenograft (Passage 1, P1) single cells were resuspended in ALDEFLUOR assay buffer. ALDEFLUOR and EPCAM positive cells (ALDH+/EPCAM+) were then detected using a flow cytometer to identify the TICs. Using the negative control ALDH inhibitor, DEAB (1.5 μM), identify the ALDH+ cells compared with background. For limited dilution (LD) in vitro spheroid assay, 5000 EPCAM+/ALDH+ and ALDH- cells were cultured in ultra-low attachment plates in cancer stem-cell medium (DMEM-F12; 1X B-27, βEGF, βFGF, 1% penicillin/streptomycin, BSA, heparin, β-mercaptoethanol). For LD in vivo study, EPCAM+ ALDH sorted cells were implanted subcutaneously with Matrigel and closely observed. Droplet Digital PCR was conducted using the QX200 Droplet Digital PCR System. miR-145 PCR was performed using TaqMan MicroRNA Assays (Applied Biosystems) and normalized to RNU6B. Results: Our LARC PDX model had high outgrowth and engraftment rates of 70 and 85% respectively and maintained critical histologic features. Both LD in vitro and in vivo experiments demonstrated that EPCAM+/ALDH+ cells were highly tumorigenic suggestive of TICs (p&amp;lt;0.05). The ALDH+ population enriched for SNAI2/ miR-145 signaling. miR-145 was inhibited by at least 8.8 fold in the TIC population. Conclusions: The lack of novel strategies plays a central role in the inability to overcome therapeutic resistance in LARC. Our results demonstrate a novel model to investigate LARC and suggest that a novel miR-145 therapeutic strategy may be able to target the TIC in LARC patients. Citation Format: Ernest R. Camp, Cindy Wang, Katie Hurst, Lourdes M. Nogueira, Victoria J. Findlay. Improving rectal cancer therapy using a patient-derived tumor xenograft model. [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 LB-043.
The autosomal genetic control of sexually dimorphic traits in humans is largely the same across the sexes
Authors: Irfahan Kassam, Allan F. McRae
Journal: Genome biology (2016)

There are substantial phenotypic differences between the male and female human. Several complex traits have recently been tested to see whether these phenotypic differences are explained by differences in genetic control between males and females. While some differences in genetic control between males and females are detected, overall the results demonstrate that the genetic control of complex traits in humans is largely the same across the sexes. Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1025-x
Evaluation of Absolute Lymphocytes: Absolute Monocytes (ALC:AMC) Ratio As Prognostic Marker in Classical Hodgkin Lymphoma Patients Treated with ABVD Chemotherapy at a Single Center in Saudi Arabia
Authors: Syed Ziauddin A. Zaidi, Ibraheem H Motabi, Shahid Iqbal, Atta Munawar Gill, Imran Khan Tailor, Nawal Faiez Alshehry, Assem A Elghazaly, Samer Homoud S Almudaibigh, Mubarak S. AlGhamdi, Ghulam Murtaza, Ahmed Butt
Journal: Blood (2015)
Abstract 1688: Mutation and gene expression analysis of circulating tumor cells (CTCs) enriched and retrieved by a sensitive microfluidic device
Authors: Yixin Wang
Journal: Cancer Research (2016)

Abstract Molecular characterization of CTCs is hindered by low sensitivity and high level of background leukocytes of currently available CTC enrichment devices and assays. We have developed a novel technology to enrich and retrieve CTCs from blood samples using a microfluidic chip. The Celsee PREP100 device captures CTCs with high sensitivity and then allows the captured CTCs to be retrieved for subsequent molecular analysis. The Celsee PREP100 system uses the microfluidic chip which has approximately 56,320 capture chambers. Based on differences in cell size and deformability, each chamber ensures that small blood cells such as red blood cells and most leukocytes escape while larger CTCs are trapped and isolated in the chambers. In the work we used the Celsee PREP100 to capture breast and lung cancer cells spiked into normal donor blood samples, including SKBR3 and NCI-H1975. We were able to show that the device can capture 20 cells with high reproducibility. The captured CTCs were retrieved from the microfluidic chip and further purified with anti-CD45 magnetic beads. Our results suggest that the cell recovery rate of this back-flow procedure is greater than 80% and the level of remaining background leukocytes is very low (about 100 cells). Work in progress to extract DNA and RNA. The resulting DNA samples are subjected to mutation analysis of a panel of cancer markers by using PCR and sequencing. The resulting RNA samples are converted to cDNAs, and gene expression analysis of selected cancer markers are carried out by using RT-QPCR. Specific DNA mutations such as EGFR exon 21 (L585R) in NCI-H1975 and mRNA expression markers including CK-19, TTF1 are tested in the retrieved cells. The sensitive and easy-to-use Celsee PREP100 system represents a promising technology for CTC capturing and molecular characterization. Clinical blood samples from patients with metastatic cancer are being tested on the Celsee PREP100 device and the results will be discussed. Citation Format: Yixin Wang. Mutation and gene expression analysis of circulating tumor cells (CTCs) enriched and retrieved by a sensitive microfluidic device. [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 1688.
Mechanisms of exertional dyspnoea in symptomatic smokers without COPD
Authors: Amany F. Elbehairy, Jordan A. Guenette, Azmy Faisal, Casey E. Ciavaglia, Katherine A. Webb, Dennis Jensen, Andrew H. Ramsook, J. Alberto Neder, Denis E. O'Donnell
Journal: European Respiratory Journal (2016)

Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown. Detailed pulmonary function tests and sensory–mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMG di ) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls. Smokers (mean± sd post-bronchodilator forced expiratory volume in 1 s (FEV 1 )/forced vital capacity 75±4%, mean± sd FEV 1 104±14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8±1.8 versus 2.6±1.1%·L −1 ) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19±11 versus 12±7% at 5 Hz) than controls (p&lt;0.05). Smokers had significantly (p&lt;0.05) lower peak oxygen uptake (78±40 versus 107±45% predicted) and ventilation (61±26 versus 97±29 L·min −1 ). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p&lt;0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMG di /maximal EMG di ) were also increased (p&lt;0.05) mainly reflecting the reduced denominator. Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm.
Abstract 3833: Restoration of wildtype structure and function of mutant p53 by thiosemicarbozones using a novel zinc metallochaperone based mechanism
Authors: Xin Yu, Adam R. Blanden, Ashley T. Tsang, Saif Zaman, John Gelleran, David Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo
Journal: Cancer Research (2016)

Abstract NSC319726 (ZMC1) is a small molecule that reactivates mutant p53 by restoration of WT structure and function to the most common p53 missense mutant (p53-R175H). We identified that ZMC1 functions as a zinc-metallochaperone, providing an optimal concentration of zinc to facilitate proper folding of p53 protein, and increasing cellular reactive oxygen species to transactivate the newly conformed p53-R175H (via post-translational modifications). ZMC1 was identified from an in silico screen of the NCI anti-cancer drug screen along with two other thiosemicarbazones (TSCs), NSC319725 and NSC328784. We investigated these TSCs to determine if they could reactivate mutant p53 using a zinc metallochaperone mechanism. We found that indeed these compounds could reactivate mutant p53 by functioning as zinc metallochaperones. In distinction, Triapine the only TSC in clinical development, does not function as a zinc metallochaperone and is not a mutant p53 reactivator. Citation Format: Xin Yu, Adam R. Blanden, Ashley T. Tsang, Saif Zaman, John Gelleran, David Augeri, S. David Kimball, Stewart N. Loh, Darren R. Carpizo. Restoration of wildtype structure and function of mutant p53 by thiosemicarbozones using a novel zinc metallochaperone based mechanism. [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 3833.
A Phase I/II Trial of Radioimmunotherapy (RIT) with 90Yttrium-Ibritumomab Tiuxetan (Zevalin®; 90Y-Zevalin) Combined with the Redox-Active Agent Motexafin Gadolinium (MGd): Prompt and High Remission Rates in Patients with Rituximab-Refractory Non-Hodgkin’s Lymphoma (NHL).
Authors: Andrew M. Evens, Stewart Spies, David Patton, Irene Helenowski, Borko Jovanovic, Sarah Miyata, Elizabeth Hamilton, M. Wayne Saville, Richard A. Miller, Jane N. Winter, Leo I. Gordon
Journal: Blood (2007)
Ubiquitin-specific peptidase 2 as a potential link between microRNA-125b and psoriasis
Authors: T. Wei, L. Folkersen, E. Biskup, N. Xu, V. Manfe, O. Niazi, R. Gniadecki
Journal: British Journal of Dermatology (2016)

The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. miR‐125b has previously been shown to be strongly associated with psoriasis, and presents as an obvious candidate for further investigation. To elucidate the specific pathway and mechanism of interest in this association. A three‐step bioinformatical hypothesis‐generation pipeline was performed to identify genes of interest. This pipeline was based on miR‐125b binding, expression in psoriatic lesions and genome‐wide association study‐based evidence of involvement. The identified candidate gene was then carefully evaluated using luciferase binding assays, in vitro overexpression, small interfering RNA knock‐down and downstream gene readouts. Based on our bioinformatical pipeline, ubiquitin‐specific peptidase 2 was selected as a likely candidate for a mechanistic explanation for psoriasis association. After establishing a definite connection to miR‐125b, we proceeded to show that modulation of nuclear factor kappa B‐mediated inflammation is the likely mechanism through which this miRNA gene pair functioned. Shedding further light on the multifactorial causes of psoriasis is essential, if the goal is to progress towards finer control of therapeutic tools in disease management. Findings, such as the ones presented herein, are therefore necessary in order to achieve the future of personalized medicine.
Abstract 1763: Body size and incidence of TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer
Authors: Thomas Ahearn, Rebecca E. Graff, Andreas Pettersson, Claire Pernar, Sarah C. Markt, Kathryn M. Wilson, Michelangelo Fiorentino, Massimo Loda, Edward L. Giovannucci, Lorelei A. Mucci
Journal: Cancer Research (2016)

Abstract Background: Evidence suggests that genetic, lifestyle, and hormonal factors are differentially associated with the incidence of TMPRSS2:ERG fusion-positive and fusion-negative tumors, suggesting that these molecular subtypes have distinct etiologies. There is scant literature on whether anthropometrics are differentially associated the risk of developing fusion-positive and fusion-negative prostate cancer. Methods: We examined the associations between adult height, recalled BMI at age 21, and updating BMI over time with risk of prostate cancer defined by TMPRSS2:ERG subtype using a prospective cohort of 49,372 men from the Health Professionals Follow-up Study. Tumor TMPRSS2:ERG status was assessed by ERG immunohistochemistry on tissue microarrays constructed from radical prostatectomy of the prostate specimens. We utilized multivariable competing risks models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of fusion-positive disease and, separately, fusion-negative disease. Results: During 23 years of follow-up, we identified 5,847 total prostate cancer cases. Among them, 2,402 were treated with RP, of whom 913 (15.6% of all cases) were assayed for ERG status. Height (per 5 inches) was positively associated with the risk of developing ERG-positive prostate cancer (HR = 1.24, 95% CI 1.03-1.50), but not associated with ERG-negative disease (HR = 0.98, 95% CI = 0.82-1.18, Pheterogenity = 0.07). Updated BMI (per 5 kg/m2) was inversely associated with the risk of developing ERG-positive disease (HR = 0.86, 95% CI = 0.74-1.00), but not associated with ERG-negative disease (HR = 1.03, 95% CI = 0.90-1.18, Pheterogenity = 0.07). BMI at age 21 was not differentially associated with the risk of developing ERG-positive or ERG-negative disease. Conclusion: Our results suggest that height and obesity are differentially associated with the risk of developing fusion-positive and fusion-negative prostate cancer. Citation Format: Thomas Ahearn, Rebecca E. Graff, Andreas Pettersson, Claire Pernar, Sarah C. Markt, Kathryn M. Wilson, Michelangelo Fiorentino, Massimo Loda, Edward L. Giovannucci, Lorelei A. Mucci. Body size and incidence of TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer. [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 1763.
Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder
Authors: Anouk Schrantee, Hyke G. H. Tamminga, Cheima Bouziane, Marco A. Bottelier, Esther E. Bron, Henk-Jan M. M. Mutsaerts, Aeilko H. Zwinderman, Inge R. Groote, Serge A. R. B. Rombouts, Ramon J. L. Lindauer, Stefan Klein, Wiro J. Niessen, Brent C. Opmeer, Frits Boer, Paul J. Lucassen, Susan L. Andersen, Hilde M. Geurts, Liesbeth Reneman
Journal: JAMA Psychiatry (2016)

Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system.To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function.A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status.Treatment with either methylphenidate or a matched placebo for 16 weeks.Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses.Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03).We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up.identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.