tbuckley/cabot-search huggingface dataset:
Abstract 2494: Vaccine-induced TNF alpha producing T cells synergize with cisplatin in tumor eradication
Authors: Cornelis J. Melief, Tetje C. van der Sluis, Sjoerd H. van der Burg
Journal: Cancer Research (2015)

Abstract Previously we have shown that Synthetic Long Peptide (SLP) vaccination against Human Papilloma Virus (HPV) oncogenic proteins is safe and induces functional T-cell responses in mice and humans. Although vaccination induces potent clinical responses in mice and in patients with premalignant lesions, no clinical responses were observed in patients with cervical cancer. Here we show in a preclinical mouse model for HPV induced malignancies that SLP vaccination can be safely combined with clinically relevant chemotherapeutics to eradicate tumors. In mice that received either peptide vaccination or chemotherapy, only a temporary regression in tumor size was observed. Importantly, combined chemo-immunotherapy induced complete and sustained tumor eradication in nearly all mice. The chemotherapeutic agent cisplatin displayed the strongest synergy with SLP vaccination. Long term regression of tumors occurred at both the maximal tolerated dose of cisplatin and at 40% of that dose when combined with SLP vaccination, but at the later dose side effects such as body weight loss were absent. Upon vaccination tumors were highly infiltrated with Tumor Necrosis Factor alpha (TNFα) and Interferon gamma (IFN-γ) producing CD8+ CTLs. Tumor cells incubated with these cytokines and cisplatin in vitro strongly enhance their chemokine expression, compatible with the abundant leukocyte infiltration into the tumor upon combined chemo-immunotherapy. Accordingly, when combined with cisplatin treatment, SLP vaccine-induced CTLs appeared to migrate earlier from the tumor rim into the tumor beds. Moreover, analysis of the tumor cells in vivo showed that combined treatment significantly decreased the proliferative capacity of tumor cells compared to single treated or untreated tumors. Furthermore, we showed that TNFα enhanced cisplatin- induced, JNK dependent tumor cell apoptosis. This cell death was accompanied by an increased expression of pro-apoptotic molecules. The synergy between cisplatin and SLP vaccination was largely abolished by in vivo treatment with monoclonal antibody against TNFα. Together, our data show that combined peptide treatment with cisplatin leads to superior tumor eradication in the absence of T cell immunosuppression. Citation Format: Cornelis J. Melief, Tetje C. van der Sluis, Sjoerd H. van der Burg. Vaccine-induced TNF alpha producing T cells synergize with cisplatin in tumor eradication. [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 2494. doi:10.1158/1538-7445.AM2015-2494
Abstract 1568: Detection of HBV-host junction DNA sequences in urine of patients with HBV-infected HCC
Authors: Selena Lin, Benjamin Song, Evan Trauger, Malcolm Hoffman, Emilie Thompson, Rebecca Zhou, Surbhi Jain, Wei Song, Ying-Hsiu Su
Journal: Cancer Research (2015)

Abstract Hepatitis B virus (HBV) related liver diseases often progresses from hepatitis to cirrhosis and eventually to hepatocellular carcinoma (HCC), which has a poor prognosis, mostly due to late detection. Chronic HBV infections are associated with &amp;gt;50% of HCC cases worldwide, and up to 90% of HBV-related HCCs (HBV-HCC) were found to contain integrated HBV DNA. During infection, HBV DNA integrates in the host chromosome at variables sites, generating a unique HBV-host junction sequence (HBV-JS) that can serve as a DNA finger print of an infected hepatocyte. During hepatocarcinogenesis, tumorigenic hepatocyte(s) undergo uncontrolled clonal expansion resulting in one to few particular HBV-JS's becoming dominant. Thus, we hypothesize that the appearance of expanded HBV-JS species is a marker of clonal expansion and can be a potential marker for early detection of HBV-HCC. A PCR-based enrichment assay and next generation sequencing (NGS) approach were developed for the HBV DR1-2 integration hotspot region to explore the feasibility of detecting HBV-JS's in the circulation (i.e. urine) of patients with HBV-HCC. HBV-HCC tissue DNA samples underwent library construction and were enriched for DNA containing the HBV DR1-2 sequences. Enriched DNA fragments were then cloned and sequenced, from which 5 HBV-JS's were discovered at Chr5 (hTERT promoter), Chr7 (AOAH intronic transcript 1), Chr12 (KCN2), Chr19 (miRNA 512-1,-2), and Chr22 (LARGE) in four patient samples. These sites were further confirmed in matched urine DNA samples by designing primers to amplify the HBV-JS. The NGS approach, which includes HBV-HCC (n = 18), HBV-hepatitis (n = 5), and HBV-cirrhosis (n = 8) urine samples to identify HBV-JS’s, is in progress. Overall, this would be the first study both to demonstrate unambiguous detection of HBV-JS's in the urine of HBV-HCC patients and to suggest the potential of detecting expanded HBV-JS species in urine as a marker for HBV-HCC screening. Furthermore, if successful, the high-throughput detection of HBV-JS's in urine by NGS offers a promising noninvasive HBV-HCC screening platform, as well as provides insight into the carcinogenic mechanisms of HBV DNA integration. Citation Format: Selena Lin, Benjamin Song, Evan Trauger, Malcolm Hoffman, Emilie Thompson, Rebecca Zhou, Surbhi Jain, Wei Song, Ying-Hsiu Su. Detection of HBV-host junction DNA sequences in urine of patients with HBV-infected HCC. [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 1568. doi:10.1158/1538-7445.AM2015-1568
644. Anterior Chamber Associated Immune Deviation (ACAID) Regulates Anti-Transgene Cellular Immune Responses Following Systemic Gene Transfer
Authors: Quentin Khebizi, Sabrina Donnou, Julie Vendomele, Mirella Mormin, Catherine Poinsignon, Séverine Cire, Anne Galy, Sylvain Fisson
Journal: Molecular Therapy (2015)

Anterior Chamber-Associated Immune Deviation (ACAID), is an antigen specific peripheral immunomodulatory mechanism described when an antigen is introduced into the anterior segment of a mammalian eye. It is not known if the ACAID mechanism could impact on cellular immune responses induced by gene therapy. Our study was therefore conducted in a murine model to evaluate if ACAID mechanism induced in the eye would induce immune tolerance to the product of a transgene injected by systemic route (i. v.) and if this could impact on the destruction of the transduced cells. To test this hypothesis, we have developed a murine model of ACAID by injecting intracameraly soluble peptides (DBY and UTY) of the HY male antigen into wild type female C57Bl/6 mice (H-2b background), followed by an intravenous injection of a recombinant AAV2/8 vector (rAAV2/8-GFP-HY) containing a transgene coding for a fusion GFP-HY molecule. In control animals (without prior ocular peptide injection), a clear transgene-specific immune response develops following rAAV2/8-GFP-HY injection as measured by spleen IFNγ ELISpot analysis, evaluation of T cell polarization profile by cytokine secretion titration and induction of CD8+ T cell destructive response by in vivo cytotoxic assays. In contrast, the number of IFNγ producing spleen cells was reduced up to 80% in ACAID conditions. In addition, cytokine secretion assays showed an impairment of the Th1 profile in ACAID condition with a reduction in the secretion of IFNγ and TNFα (8 and 2 times lower, respectively). Moreover, a model of in vivo cytotoxic assay suggests that almost all HY-expressing cells can survive in ACAID-induced mice in contrast to the control mice. In conclusion, cytokine and in vivo cytotoxic assays indicate that ACAID seems to be a powerful inhibitory mechanism in the context of systemic gene transfer, limiting cellular immune responses against the transgene and promoting transgene expressing cells survival.
Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up
Authors: Anna Gref, Simon K. Merid, Olena Gruzieva, Stéphane Ballereau, Allan Becker, Tom Bellander, Anna Bergström, Yohan Bossé, Matteo Bottai, Moira Chan-Yeung, Elaine Fuertes, Despo Ierodiakonou, Ruiwei Jiang, Stéphane Joly, Meaghan Jones, Michael S. Kobor, Michal Korek, Anita L. Kozyrskyj, Ashish Kumar, Nathanaël Lemonnier, Elaina MacIntyre, Camille Ménard, David Nickle, Ma'en Obeidat, Johann Pellet, Marie Standl, Annika Sääf, Cilla Söderhäll, Carla M. T. Tiesler, Maarten van den Berge, Judith M. Vonk, Hita Vora, Cheng-Jian Xu, Josep M. Antó, Charles Auffray, Michael Brauer, Jean Bousquet, Bert Brunekreef, W. James Gauderman, Joachim Heinrich, Juha Kere, Gerard H. Koppelman, Dirkje Postma, Christopher Carlsten, Göran Pershagen, Erik Melén
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns.In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc β-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression.Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.
Abstract 2224: Functional role of NRF2 signaling in sphere cultured carcinoma cells
Authors: In-geun Ryoo, Mi-Kyoung Kwak
Journal: Cancer Research (2015)

Abstract Cancer stem cells (CSCs) are known to express high levels of antioxidant proteins and ABC transporters. In this study, we investigated the potential involvement of NF-E2-related factor 2 (NRF2) in CSC survival and stress response by using the MCF7 mammosphere culture, which is accepted as a CSCs-enriched system. The levels of NRF2 protein, reporter transcription activity, and target gene expression such as efflux transporters were higher in mammospheres than in the monolayer. We observed that proteasome activity as well as catalytic subunits expression was decreased in the mammospheres. Additionally, mammospheres showed an elevated p62 protein level and p62-knockdown suppressed NRF2 activation. The role of NRF2 in mammospheres could be demonstrated in NRF2-knockdown mammospheres. Sphere growth was retarded in knockdown group and anticancer drugs resistance was not obtained in NRF2-knockdown mammospheres in contrast to the control mammospheres. NRF2 activation could be confirmed in spheres-culture of colon cancer and ovarian cancer cells. These results show that reduced proteasome function and elevated p62 level contributed to NRF2 activation in CSCs-enriched mammospheres. The study further suggests a potential role of NRF2 in CSCs survival and stress resistance. Citation Format: In-geun Ryoo, Mi-Kyoung Kwak. Functional role of NRF2 signaling in sphere cultured carcinoma cells. [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 2224. doi:10.1158/1538-7445.AM2015-2224
PP-014 Control of receptor expression in vagal afferent neurons by activation of cannabinoid 1 receptors
Authors: G Burdyga, R Dimaline, D G Thompson, A Varro, G J Dockray
Journal: Gut (2010)

<h3>Introduction</h3> The intestinal hormone cholecystokinin (CCK) inhibits food intake via stimulation of vagal afferent neurons (VAN). In fasted rats, there is increased synthesis of the endocannabinoid anandamide (AEA) in the small intestine, and of its receptor (CB1) in VAN. Peripheral AEA stimulates food intake via VAN and endogenous CCK inhibits expression of CB1. The aim of the present studies was to characterise CB1 expression in VAN and to determine the functional significance of stimulation of these receptors. <h3>Methods</h3> Nodose ganglion neurons expressing CB1 were detected by immunohistochemistry or in situ hybridisation in rats following dietary manipulation or administration of drugs and hormones ip. Similar approaches were used for MCH1 and Y2 receptor expression. <h3>Results</h3> Expression of CB1 in rat VAN was detectable within 6 h and increased to a maximum after 24 h of fasting when approximately 50% of neurons in the mid- and caudal regions expressed the receptor. In contrast, MCH1R, which is also associated with orexigenic signalling, showed a delayed increase in expression compared with CB1 while Y2R, associated with satiety signalling, exhibited decreased expression with fasting. Administration of CCK8s (10 nmol) to fasted rats decreased expression of CB1 and MCH-1 but the t1/2 for loss of CB1 was approximately 1 h compared with 3 h for MCH-1. The action of CCK was inhibited by ghrelin and orexin-A. The CB1 agonist AEA (10 mg) had ghrelin-like actions in reversing the effect of CCK on CB1, MCH1 and Y2 receptor expression. In contrast, in rats fasted for 18 h, administration of a CB1 antagonist/inverse agonist (AM281, 0.25 mg) downregulated CB1 expression and increased Y2 receptor expression. <h3>Conclusion</h3> Activation of CB1 on vagal afferent neurons determines the pattern of expression of receptors in these neurons indicating a new and hitherto unrecognised role for endocannabinoids in gut-brain signalling.
Sleeping on the Street
Authors: Deborah Grady
Journal: JAMA Internal Medicine (2016)

duration averaged only 30 minutes per day, yet 33% of homeless persons complained of daytime fatigue compared with 15% of the general population.Among the homeless persons, 25% reported that they regularly took a drug to help them sleep vs 15% of controls.Discussion | Our survey shows that in France, homeless people sleep less and are more likely to have insomnia and daytime fatigue than persons in the general population.Sleep is important for good health 1,2 and necessary to the ability to work and successfully perform daily activities.Improving the quality and duration of sleep in the homeless may, therefore, improve alertness, health, and the ability to face daily tasks.We believe that improving sleep deserves more attention in this vulnerable group.We strongly support strategies other than hypnotic agents to improve sleep in the homeless, including more careful control of noise, lighting, heating, and air conditioning at night.Facilities could provide residents with sleep aids, such as earplugs, eye sleep masks, and pillows.Screens between beds could offer some sense of privacy, even in collective dormitories, and addressing issues of personal security should promote better sleep.Ideally, housing facilities would provide individual rooms, but collective shelters might be better organized with specific architecture and schedules to promote sleep.
Combined Treatment with Bortezomib Plus Bafilomycin A1 Enhances Cytocidal Effect along with Induction of ER Stress In Myeloma Cells: Crosstalk Among Proteasome, Autophagy-Lysosome, and ER Stress
Authors: Keisuke Miyazawa, Shota Moriya, Tomohiro Kawaguchi, Tadashi Ohtomo, Xiao-Fang Che, Munekazu Naito, Masahiro Itoh, Akio Tomoda
Journal: Blood (2010)
Abstract 5141: A comprehensive system of congenic mouse melanoma models for evaluation of immune therapies
Authors: Katrina M. Meeth, William E. Damsky, Marcus Bosenberg
Journal: Cancer Research (2015)

Abstract There has been longstanding interest in the relationship between the immune system and malignant melanoma, the deadliest form of skin cancer. Melanoma has been the tumor of choice for the evaluation of a wide variety of therapeutic approaches that rely on stimulation of the immune system to combat cancer. The striking responses to immune checkpoint inhibitors noted in some melanoma patients have now been observed in several other malignancies, including renal cell carcinoma, lung cancer, and prostate cancer. These findings are very encouraging, however the specific mechanisms of response and reasons why only a subset of patients respond to therapy are not known. The extraordinary potential of immune therapies in cancer suggests that human-relevant mouse models of cancer are required to understand mechanisms of response and to optimize therapy so that a larger proportion of patients respond. We have generated and evaluated a series of genetically engineered mouse models driven by alterations in Braf, Pten, Cdkn2a, beta catenin, p53, and Nras that reflect the genetic diversity of the vast majority of human melanoma. We have backcrossed 6 of these models to C57Bl/6, generated tumors, and isolated a series of over 20 congenic mouse melanoma cell lines. Several independent lines have been isolated for each melanoma genotype generated. Injection of these lines into C57Bl/6J mice results in reproducible tumor formation in the absence of co-injection of Matrigel. We are in the process of characterizing the tumor microenvironment in each of the models using flow cytometry and a novel quantitative imaging approach of histological sections, which produces flow cytometry-like data, but retains spatial and morphologic information that can be utilized to characterize much smaller tumors. This series of congenic lines represents an ideal set of models for the study of cancer immunology and responses to immune therapies. Citation Format: Katrina M. Meeth, William E. Damsky, Marcus Bosenberg. A comprehensive system of congenic mouse melanoma models for evaluation of immune therapies. [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 5141. doi:10.1158/1538-7445.AM2015-5141
P233 A pilot diagnostic cardio-respiratory breathlessness clinic: can a symptom-based approach achieve an earlier diagnosis?
Authors: I Valero-Sanchez, S Khatri, W Nicolson, H Seth, R Walton, DP Jackson, MC Steiner, RA Evans
Journal: Thorax (2016)

<h3>Introduction</h3> We aimed to compare the time to diagnosis and treatment between a combined cardio-respiratory diagnostic breathlessness clinic (BC) and usual specialist outpatient care (UC) in patients with chronic breathlessness referred from primary care. <h3>Methods</h3> We surveyed patients with undifferentiated chronic breathlessness referred to secondary care outpatient cardiology and respiratory services during March 2015 (UC). Subsequently, we implemented a fortnightly pilot breathlessness clinic (BC) between August 2015 and January 2016 using existing referrals to either cardiology or respiratory specialties. Patients were seen by either a consultant cardiologist or respiratory physician, reviewed by a physiotherapist, and discussed by the MDT at the end of clinic. The investigations performed in primary care were documented and where needed the following investigations were completed for the BC: haemoglobin, brain natriuretic peptide, spirometry, electrocardiogram, chest radiograph, Nijmegen questionnaire, screening for anxiety and depression symptoms and a physical activity questionnaire. Time to diagnosis, physiotherapy, treatment and discharge were measured and compared with UC. Patients were requested to complete a patient experience questionnaire. <h3>Results</h3> Table 1 shows the results of UC compared to the BC. 35% of referrals from primary care reported ≤1 investigation and only 28% had had spirometry performed. The MRC dyspnea scale grade distribution in the BC was MRC1 = 4%, MRC2 = 30%, MRC3 = 37%, MRC4 = 22%, MRC5 = 7%. Co-morbidity was common with over &gt;80% of patients having at least two diagnoses contributing to their breathlessness. Dysfunctional breathing was the commonest primary and secondary diagnosis. 18.5% of patients in the BC could have been diagnosed in primary care. 18.5% were originally referred to the incorrect specialty and in nearly 30% of patients referrals to the other specialty were potentially avoided due to the MDT discussion. Only one third of patients required specialist tests to secure their diagnosis. All patients rated their experience as ‘excellent’. <h3>Conclusions</h3> Our pilot diagnostic breathlessness clinic reduced time to diagnosis and treatment, and avoided further between-specialty outpatient appointments. However, our results demonstrate the need for symptom-based breathlessness pathways starting in primary care to utilise simple investigations prior to referral to specialist clinics. <h3>Reference</h3> Valero I, <i>et al</i>. Abstract accepted ERS, 2016.
Percutaneous nephrolithotomy (PCNL) under local infiltrative anesthesia with and without stand-by anesthesia – Complication rates and clinical outcome for a method at the exploration stage according to IDEAL
Authors: T.H. Ecke, G. Weingart, C. Lange, S. Hallmann, F. Wawroschek, D. Barski, J. Ruttloff, H. Gerullis
Journal: International Journal of Surgery (2016)