tbuckley/cabot-search huggingface dataset:
OT-08 * DISTINCT BRAIN LINEAGE AND STROMAL GENE EXPRESSION PATTERNS IN WNT, SHH, GROUP 3 AND GROUP 4 MOLECULAR SUBGROUPS OF PEDIATRIC MEDULLOBLASTOMA
Authors: A. Achrol, T. Liu, H. Vogel, S. Chang, M. Edwards, G. Harsh, D. Sahoo
Journal: Neuro-Oncology (2015)

Medulloblastomas are the most common malignant brain tumors in children, comprising distinct molecular subgroups that differ in neuroanatomical predilection, clinical characteristics and overall survival. Here we compare genetic brain lineage and stromal immune profiling in N = 558 pediatric medulloblastomas against N = 426 adult glioblastomas. The medulloblastoma cohort included N = 114 SHH (20%), N = 34 WNT (6%), N = 156 Group 3 (28%), and N = 254 Group 4 (46%). Genetic brain lineage analyses revealed WNT and SHH medulloblastoma to be distinctly astrocytic and astroglial; more similar to adult mesenchymal/classical glioblastoma than other pediatric medulloblastoma. In contrast, Group 4 was distinctly neuronal and oligodendrocytic; more similar to adult proneural/neural glioblastoma than other pediatric medulloblastoma. Interestingly, Group 3 demonstrated no brain lineage enrichment-unlike any other pediatric or adult brain tumor subtype-suggesting a non-CNS etiology for this subgroup known for distinctive large-cell anaplastic histology, aggressive behavior, and uniquely high incidence of metastatic disease. Analysis of stromal immune signatures revealed significant macrophage-specific enrichment in WNT and SHH, but not Group 3 and 4 tumors. These myeloid signatures were characteristic of M2-polarized macrophages, unlike adult glioblastomas, which enriched in both M1 and M2 signatures. While myeloid responses in adult glioblastoma were predictive of poor overall survival, the opposite was true in pediatric medulloblastoma-with improved survival in children with robust immune responses. These data demonstrate that medulloblastoma subtypes display distinct brain lineages and share greater similarities to adult glioblastomas than other pediatric medulloblastomas, further supporting distinct cellular origins for each subtype. Furthermore, innate immune responses were distinctive between subtypes and, in contrast to adult tumors, predictive of good outcomes, suggesting prognostic significance of immune responses differs in children versus adults. Taken together, these findings highlight the distinctiveness of medulloblastoma subtypes with important clinical implications for the design of future targeted molecular therapy and immunotherapy trials in pediatric and adult brain tumor patients.
A retrospective review of breast cancer patients with central nervous nystem metastasis treated with capecitabine
Authors: M. Kurt, S. Aksoy, M. Hayran, N. Guler
Journal: Journal of Clinical Oncology (2007)

1098 Background: In all of the major studies on the effects of capecitabine in metastatic breast cancer (MBC) patients with central nervous system (CNS) metastasis were categorically excluded, understandably due to the poor outcome associated with such advanced disease, and as a consequence, the data are limited on such cases. The aim of this study was to evaluate the effectiveness and toxicity of capecitabine in breast cancer patients with CNS metastasis. Methods: The records of all patients with MBC presenting to the Department of Medical Oncology at Hacettepe University Hospital, Ankara, Turkey, for treatment between December 2001 and December 2005 were evaluated. Patients who recieved capecitabine as a sole agent for MBC with CNS metastasis were included in the study. All patients recieved capecitabine at a dose of 2,500mg/m 2 /day for 14 days at 3 weeks intervals. Results: Twenty patients were included in this retrospective analysis. All were female with a median age of 38 years (range, 20–58) at the diagnosis and the median time to brain metastasis was 3.9 years (range, 0.5–19.6). Three patients had undergone surgery for CNS metastasis, and all patients had recieved whole brain radiotherapy before the capecitabine treatment. A total of 159 cycles of chemotherapy were introduced and for each patient median number of chemotherapy cycles were 6.5 (range 1–28 cycles). Nine of them were given capecitabine as first-line chemotherapy after brain metastasis. There were 2 (10%) complete (one patient had metastasectomy for brain metastasis), and 7 (35%) partial responses with 6 (30%) patients having stable disease. Progressive disease was observed in 5 (25%) patients. Overall response rate was 45%. Median progression free survival time was 7.3 months (range 1.8–26.7). Adverse effects were seen in 13 patients, with grade 3 hand food syndrome occuring in 5 patients resulting in dose reduction. Grade II neutropenia was observed in 1 patient. Conclusions: Capecitabine is effective and well tolerated in the treatment of breast cancer patients with CNS metastases. No significant financial relationships to disclose.
Abstract 697: Inhibition of Cancer Progression by Upregulation of the Opioid Growth Factor (OGF) - OGF Receptor (OGFr) Axis Using Imquimod or Low Dose Naltrexone
Authors: Patricia J. McLaughlin, Jaimon Stucki, Ian S. Zagon
Journal: Cancer Research (2010)

Abstract Opioid growth factor (OGF, [Met5] enkephalin), is a tonically active, negative growth factor, and interacts with a nuclear-associated receptor, OGFr. The OGF-OGFr axis mediates cell proliferation by targeting cyclin-dependent kinase inhibitory pathways. Overexpression of OGFr by pharmacological modulation of several human cancer cell lines in tissue culture has been shown to result in decreased cell replication in response to either elevated endogenous OGF or exogenous administration of this inhibitory peptide. The present study examines tumor progression in nude mice whereby established tumors of human squamous cell carcinoma of the head and neck are treated by 2 methods of upregulation of the OGF-OGFr axis: imiquimod or low dosages of the opioid antagonist naltrexone (LDN; 0.1 mg/kg naltrexone). Tumor volume was monitored 3 times weekly. Some tumors were assessed for immunohistochemical levels of OGF and OGFr. Imiquimod, a promoter of OGFr gene activity, was administered topically either 1X or 3X each week. LDN was given systemically 1X or 3X per week, or daily. At the time of death, tumor volumes for the 1X and 3X imiquimod treated mice were 18 and 47%, respectively, smaller than controls, and tumor weights were decreased 36 and 43%, respectively relative to controls. All LDN treatment regimens effectively reduced tumor volume relative to mice receiving vehicle, with a regimen-related decrease in tumor growth noted throughout the study. At termination on day 35, mean tumor volumes of mice exposed to LDN were reduced from vehicle-treated controls by 35%, 61% and 84% when given 1X/week (p&amp;lt;0.05), 3X/week (p&amp;lt;0.001) and daily (p&amp;lt;0.001), respectively. Tumor masses at the time of termination were 42%, 60%, and 89% smaller in the 1X/week, 3X/week, and daily, respectively, LDN treatment groups relative to controls. Semi-quantitative immunohistochemical analysis of OGF levels in tumor tissue revealed marked elevations of peptide following either imiquimod or LDN therapy. OGF tissue levels were elevated 70% and 95% in tissue from mice treated with 3X/week imiquimod or 3X/week LDN, respectively, relative to mice receiving vehicle. In summary, modulation of the OGF-OGFr axis provides new and novel therapeutic strategies for the treatment of human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 697.
Lead poisoning
Authors: Barbara J Bain
Journal: American Journal of Hematology (2014)

Examination of the patient showed a lead line on her gums and serum lead was 82 μg/100 ml. The source of lead in this patient was not discovered but she recovered on moving to England. Acknowledged sources of lead are Indian cosmetics and ayurvedic medicines, not only those available in India but also those manufactured in the USA and sold via the internet 1. Hematological effects of lead poisoning include a hypochromic microcytic anemia with sideroblastic erythropoiesis, a hemolytic anemia and a leucoerythroblastic blood film. The cause of the well known basophilic stippling and the hemolysis is inhibition of pyrimidine 5′nucleotidase while the hypochromic microcytic anemia and sideroblastic erythropoiesis are due to inhibition of enzymes involved in heme synthesis. Although lead poisoning is uncommon in most developed countries, haematologists should be alert to the possibility that alternative medications and food supplements containing lead may have been purchased during travel or via the internet. Other causes of lead poisoning include occupational exposure (battery production, foundry work, painting and construction, mining), retained bullets, and exposure to lead-based paints in older, poorly maintained houses (sometimes through pica) 2, 3. In developing countries sources of lead are much more widespread than in Western countries and include, in addition to traditional medicines, cosmetics and tooth-cleaning powders, the ongoing use of lead-based paints, water contamination from lead pipes and cisterns, use of lead-containing cookware and lead-glazed crockery, and unsafe practices in small factories and mines 3, 4.
THU0059 Identification of New Differentially Methylated Genes That Have Potential Functional Consequences in Primary Sjogren Syndrome
Authors: Y. Cheng, C. Huang
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Primary Sjögren9s syndrome (pSS) is a systemic autoimmune disease with incompletely understood etiology. Very little is known about the role of epigenetic dysregulation in the pathogenesis of pSS. Recently, Global DNA methylation profiles have been gradually surfaced to the ground, however, there are not studies in terms of global DNA methylation alterations in the pSS. We hypothesize that there DNA methylation profiles in pSS, which may be identified using higher resolution assay methods. <h3>Objectives</h3> Objectives: To investigate Global DNA methylation profiles of SS patients. <h3>Methods</h3> We used the newly developed illumina HumanMethylation 450 BeadChip in the blood of 3 Sjogren syndrome and 3 healthy controls and combined these with gene expression data for identifying new DNA methylation that may have functional consequences in pSS development and progression. We also confirmed our methylation results in an independent data set. Two aberrant DNA methylation genes were validated among an additional 56 PCa samples and 55 adjacent normal tissues. <h3>Results</h3> A total of 472139 CpG sites showed significant differences in DNA methylation (FDR adjusted P,0.05), defined as a mean methylation difference of at least 20% between PCa and normal samples. Furthermore, a total of 122 genes had more than one differentially methylated CpG site in their promoter region and a gene expression pattern that was inverse to the direction of change in DNA methylation (e.g. decreased expression with increased methylation, and vice-versa).Pathway analsis reveals methylation difference in MAPK signaling, Wnt signaling, p53 signaling, Calcium signaling,Chemokine signaling, Antigen processing and presentation, B cell receptor,T cell receptor signaling, Salivary secretion, VEGF signaling, TGF-beta signaling Toll-like receptor signaling and Jak-STAT signaling pathway Other relevant genes such as CD247, TNFRSF25, PTPRC, GSTM1 and PDCD1 were also hypomethylated. The interferon signature pathway was represented by hypomethylation of STAT1, IFI44L, USP18 and IFITM1. <h3>Conclusions</h3> Conclusion: This is the first epigenome-wide DNA methylation study in pSS. Our data highlight a role for DNA methylation in pSS and identify disease-associated DNA methylation changes in several genes and pathways in naïve CD4+ T cells in pSS that may be involved in the pathogenesis of this disease. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5360
Complications and Failures of Subclavian-Vein Catheterization
Authors: P F Mansfield, D C Hohn, B D Fornage, M A Gregurich, D M Ota
Journal: New England Journal of Medicine (1995)

Although catheterization of the subclavian vein is a common procedure, the risk factors for complications and failures, with the exception of the physician's experience, are poorly understood. Ultrasonography has been recommended to help guide the placement of central venous catheters.We conducted a prospective randomized trial of ultrasound-guided location of the subclavian vein as compared with standard insertion procedures. In the group of patients undergoing catheterization with ultrasound guidance, the site of the insertion was marked before the catheterization attempt; real-time ultrasound guidance was not used. The 821 eligible patients (411 in the ultrasound group and 410 in the control group) underwent catheterization in a single procedure suite under controlled nonemergency conditions, in most cases for the administration of chemotherapy.Ultrasound guidance had no effect on the rate of complications or failures of subclavian-vein catheterization (risk ratio for complications, 1.00; 95 percent confidence interval, 0.66 to 1.52; risk ratio for failures, 1.04; 95 percent confidence interval, 0.72 to 1.50). In multivariate analyses, prior major surgery in the region (P = 0.002), a body-mass index (the weight in kilograms divided by the square of the height in meters) higher than 30 or lower than 20 (P = 0.009), and previous catheterization (P = 0.043) were associated with failed attempts. Complications were also associated with failed attempts: 52 of the 721 patients (7.2 percent) in whom catheterization was successful had complications, as compared with 28 of the 100 patients (28 percent) in whom physicians were unable to place catheters. The number of needle passes was strongly associated with the rates of failure and complications. The complication rate rose from 4.3 percent with one pass to 24.0 percent with more than two passes.Ultrasound guidance of subclavian-vein catheterization, as used in this study, was not beneficial. In patients at highest risk for complications and failures, catheterization should be attempted by the most experienced physicians available.
Pegylated interferon and ribavirin: a therapeutic option in patients who fail to respond to telaprevir-based triple therapy?
Authors: Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu
Journal: Hepatology (2013)

We read with great interest the article by Pascale et al.,1 reporting a man with chronic hepatitis C virus (HCV) genotype 1b infection who relapsed after telaprevir-based triple therapy and achieved sustained virologic response (SVR) with a subsequent 48-week course of dual therapy (peginterferon alfa/ribavirin). We think the definition of failure to respond to telaprevir-based triple therapy seems not appropriate. This patient received telaprevir, peginterferon alfa-2a, and ribavirin for only 12 weeks in the phase 2 study.2 The recommendation of the American Association for the Study of Liver Diseases (AASLD) guidelines for the therapy for genotype 1 chronic HCV infection is the use of telaprevir in combination with dual therapy for 12 weeks followed by an additional 12 weeks (for patients without cirrhosis and with extended rapid virologic response [eRVR]: undetectable HCV RNA level at weeks 4 and 12) or 36 weeks (for patients with cirrhosis or without eRVR, or recommended to stop the therapy: HCV RNA level is >1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24) of dual therapy.3 For genotype 1-naïve patients with RVR, high SVR rates have been reported previously by 24 weeks and 48 weeks dual therapy in our randomized trial (89% and 100%, respectively)4 and by Jensen et al. (89% and 91%, respectively).5 The SVR rate was 60% with the 12-week triple therapy for patients with eRVR2 and was 92% with an additional 12 weeks dual therapy.6 Since the 12-week telaprevir-based triple therapy seems to be "suboptimal," the conclusions by the authors that a reinforced regimen of dual therapy could be an option in genotype 1-naïve patients who failed to achieve SVR after 12 weeks telaprevir-based triple therapy needs further consideration. Chia-Yen Dai, M.D., Ph.D.1-3 Wan-Long Chuang, M.D., Ph.D.1,2 Ming-Lung Yu, M.D., Ph.D.1,2 1Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 2Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 3Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
A Controlled Trial of Metoclopramide in Symptomatic Gastroesophageal Reflux
Authors: R. W. McCallum, A. F. Ippoliti, C. Cooney, R. A. L. Sturdevant
Journal: New England Journal of Medicine (1977)

Since metoclopramide increases lower-esophageal-sphincter pressure in patients with gastroesophageal reflux, we compared the effects of metoclopramide, 10 mg four times daily, with those of placebo on symptoms in 31 patients with chronic heartburn. Eighteen patients completed a random-order, double-blind crossover study of two consecutive eight-week periods. The final 13 patients crossed over only if their symptoms were not substantially improved after the first eight weeks. Response of low-esophageal-sphincter pressure to metoclopramide did not correlate significantly with symptomatic improvement. After the metoclopramide treatment period, mean basal pressure was unchanged from values before study. In both treatment periods, metoclopramide-treated patients had significantly more symptomatic improvement than the control group (P less than 0.05).
Ultraviolet Sun Exposure Is Associated with the Acute Symptoms of Atopic Dermatitis in Young Children
Authors: Kangmo Ahn, Jihyun Kim, Hyunyoung Jeon, Hyunmi Kim, Youngshin Han, Kwon Jung, Sumi Eo, Mijin Ahn, Young-Min Kim
Journal: Journal of Allergy and Clinical Immunology (2016)
FRI0487 Increased Epicardial Adipose Tissue in Patients with Systemic Sclerosis
Authors: N. Yilmaz, E. Baysal, O. Karadag
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Microvasculopathy and endothelial wall damage are prominent features of Systemic sclerosis (SSc) and can increase the risk for cardiovascular disease. Epicardial adipose tissue (EAT) is localized beneath the visceral pericardium and shown to have close relationship with coronary artery disease (CAD). <h3>Objectives</h3> The goal of this study was to investigate the thickness of EAT in SSc patients, as a indirect manifestation of coronary artery disease. <h3>Methods</h3> Thirty SSc patients and 30 healthy controls (HC) were included to the study. Baseline characteristics of the patients, including age, gender, smoking status, diabetes or hypertension history, disease duration since the onset of the first non-Raynaud9s symptoms and disease subset, were recorded. Measurement of EAT was evaluated using Echocardiography and Doppler imaging. <h3>Results</h3> Both SSc patients and HC were similar in terms of having diabetes mellitus or hypertension and smoking history. EAT thickness was significantly higher in SSc group compared to HC (6.2±0.9 mm vs. 5.7±0.6 mm, p=0.01). SSc patients with digital ulcer had higher EAT thickness than without, but the difference did not reach statistical significance (0.66±0.07 vs. 0.60±0.09, respectively, p=0.07). EAT thickness was correlated with both disease activity score (r=0.52, p=0.003), and disease severity score (r=0.45, p=0.01). <h3>Conclusions</h3> This is the first study indicating significantly higher EAT-thickness and showing the relationship with disease activity, in SSc patients. We believe that further studies are needed to clarify the role of adipose tissue in patients with SSc. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1245
S123 The effect of rhinovirus infection on cough receptors on human sensory nerve and human primary bronchial epithelial cells
Authors: H. Abdullah, S. L. Cosby, L. Heaney, L. McGarvey
Journal: Thorax (2011)

Human rhinovirus (HRV), a member of the <i>picornaviridae</i> family is a single stranded RNA virus. Rhinovirus infection in non-asthmatics rarely causes serious problems. However in asthmatic subjects HRV contributes to more than 60% of asthma exacerbations where the cough reflex is hyper-reactive and provokes severe coughing and wheezing. <h3>Rational</h3> Members of a novel transient receptor potential (TRP) channels, the TRP vanilloid 1 (TRPV1), ankyrin like protein with transmembrane like domain 1 (TRPA1) and TRP melastatin 8 (TRPM8) have been shown to be involved in physiological and pathological aspects of cough. Subsequently understanding the interaction between HRV and ‘cough receptors’ is crucial as it may indicate potential therapeutic targets and strategies to block these interactions. In this study we investigated the effect of HRV infection on the cough reflex by determining the expression of receptors implicated in the cough process. We hypothesised that HRV may directly and/or indirectly interact with these receptors on sensory nerves and epithelial cells in the airways to provoke cough reflex. <h3>Methods</h3> Human primary bronchial epithelial cells (PBEC) were obtained following informed consent and the human neuroblastoma (IMR-32) cell line was used to represent the fundamental cell type which controls the reflex to cough. The IMR-32 cells undergo differentiation (dIMR-32) to acquire characteristics of peripheral nerve cells with positive neuronal markers. The expression of ‘cough receptors’ at the protein level in both cell types were detected by fluorescent staining using confocal microscopy and flow cytometry analysis. Receptors mRNA levels were measured by quantitative real-time PCR at different time points post-infection with HRV or treatment with UV-inactivated virus or supernatant. <h3>Results</h3> Both cell types dIMR-32 and PBEC were susceptible to HRV infection and showed positive staining for TRPA1, TRPV1 and TRPM8. Up-regulation of the ‘cough receptors’ mRNA occurred at low multiplicity of infection moreover, higher level of ‘cough receptors’ expression was detected in PBEC isolated from subjects with lung disease compared to healthy volunteers. <h3>Conclusions</h3> These results suggest that virus may both induce cough and interfere with cough related airway clearance depending on the level of infection at different time points.
Which is the optimal treatment for Barrett’s esophagus with high grade dysplasia – ablation or complete endoscopic removal?
Authors: N. Chai, E. Linghu
Journal: Endoscopy (2012)

We read with great interest the article by Halsey et al. [1] on the pattern and sites of recurrence of Barrett’s esophagus with high grade dysplasia (HGD) following endoscopic liquid nitrogen spray cryotherapy. The authors concluded that ultimately this method achieved a 92 % complete response rate. They also concluded that random 4-quadrant biopsy is not sufficient during surveillance for the detection of recurrent lesions, and that biopsies should be performed routinely in the area immediately below the neosquamocolumnar junction (NSCJ). We think that this article is one of the most important papers to be published in recent years for guiding endoscopists in their choice of treatment for Barrett’s HGD and for suggestions of how to follow up the patient.