tbuckley/cabot-search huggingface dataset:
Abstract B26: Therapeutic targeting of sarcomas driven by EWSR1 fusion oncogenes by modulation of the fusion oncogene pre-mRNA
Authors: Emily Slotkin, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi, Lee Spraggon
Journal: Cancer Research (2016)

Abstract Many predominantly pediatric sarcomas are driven by chromosomal translocations that generate oncogenic fusion transcription factors. The Ewing sarcoma breakpoint region 1 (EWSR1) is one of the most commonly involved genes in sarcoma translocations. This gene has a large number of fusion partners, primarily associated with the pathogenesis of Ewing sarcoma, but also with other soft tissue sarcomas. Targeting the resulting aberrant oncogenic chimeric transcription factors would provide an ideal therapy, but this has approach has proved elusive with conventional small molecule approaches. We have developed an approach to employ splice-switching oligonucleotides to redirect the pre-mRNA splicing of EWSR1 fusion transcription factors. Through targeted exon skipping, and/or activation of intronic polyadenylation, these new compounds provide a targeted therapeutic approach for EWSR1 translocation positive sarcomas and other malignancies. Citation Format: Emily Slotkin, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi, Lee Spraggon. Therapeutic targeting of sarcomas driven by EWSR1 fusion oncogenes by modulation of the fusion oncogene pre-mRNA. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B26.
IMCT-05COMBINABILITY OF TOCA FC AND TOCA 511 WITH CHEMOTHERAPY AND TARGETED AGENTS
Authors: Santosh Kesari, Joseph Landolfi, Tom Mikkelsen, Manish Aghi, Michael A. Vogelbaum, J. Bradley Elder, Charles Cobbs, Samuel Singer, Joan M. Robbins, Derek Ostertag, Doug J. Jolly, Alice Chu, Mary Rose Keller, Andreas Niethammer, Timothy F. Cloughesy
Journal: Neuro-Oncology (2015)

Investigational Toca 511, a retroviral replicating vector, and Toca FC (extended-release flucytosine) are used in combination to target recurrent high grade glioma at resection by transducing the tumor with the gene encoding cytosine deaminase, converting flucytosine to 5-FU intratumorally. Preclinically, additive efficacy with temozolomide, lomustine and radiation therapy has been observed. Patients treated on two protocols (NCT 01156584 and NCT01470794) delivering intracranial Toca 511 and Toca FC were enrolled in a continuation protocol for extended safety observations, which allows Toca FC with investigator's choice of subsequent therapy. Exploratory safety analysis of the combinability of Toca 511 and Toca FC with concurrent subsequent therapy was conducted. Five patients received Toca FC in combination with other therapies. These patients were 37-68 years old; 4 had recurrent glioblastoma and 1 recurrent anaplastic oligodendroglioma. Concurrent therapy was administered for 2 to 10 months, including Toca FC + lomustine (1), lomustine + procarbazine (1), lomustine + bevacizumab (2), sequential bevacizumab + lomustine then bevacizumab + carboplatin (1). Patients reported adverse events (AEs) ranging from Grade 1 to Grade 3. No Toca 511- or Toca FC- related serious AEs were reported. AEs related to Toca 511 occurred in 2 patients: grade 1 fatigue, generalized aching and to Toca FC in 4 patients: grade 1 fatigue, decreased appetite, nausea, constipation, diarrhea; grade 2 heartburn, nausea, vomiting, constipation. Overall survival was 11-30+ months (2 alive as of data cut-off date). Preliminary data suggest that in combination with chemotherapy and/or bevacizumab, Toca 511 and Toca FC are tolerated with a manageable safety profile. Updates with prospectively collected data on treatment with lomustine or bevacizumab will be provided. The safety of combining Toca 511 and Toca FC with multimodality treatment will be further explored in a Phase 1b in newly diagnosed glioblastoma to begin enrollment in 2016.
&lt;sc&gt;dl&lt;/sc&gt;-Serine: Promoting Activity on Renal Tumorigenesis by &lt;italic&gt;N&lt;/italic&gt;-Ethyl-&lt;italic&gt;N&lt;/italic&gt;-hydroxyethylnitrosamine in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Y Hiasa, N Enoki, Y Kitahori, N Konishi, T Shimoyama
Journal: JNCI Journal of the National Cancer Institute (1984)

Subcutaneous injection of DL-serine increased the number and size of renal tubular cell tumors in male W rats treated with 500 or 1,000 ppm N-ethyl-N-hydroxyethylnitrosamine [(EHEN) CAS: 13147-25-6, 2-(ethylnitrosamino)ethanol]. At the end of the 32-week experiment, the incidences of renal tumors were 95% in rats treated with 1,000 ppm EHEN for 2 weeks and then given three sc injections of DL-serine every 2 weeks, 33% in rats treated with 1,000 ppm EHEN for 2 weeks, and 28% in rats treated with 500 ppm EHEN for 2 weeks and then given three sc injections of DL-serine every 2 weeks. No renal tumors were found in rats treated with 500 ppm EHEN alone or given three sc injections of DL-serine alone every 2 weeks.
In Vivo Transfer of Antitumor Activity by Peritoneal Exudate Cells From Mice Treated With Corynebacterium parvum : Reduced Effect in Irradiated Recipients 2
Authors: L. J. Peters, W. H. McBride, K. A. Mason, N. Hunter, I. Bašić, L. Milas
Journal: JNCI Journal of the National Cancer Institute (1977)

Experiments were undertaken to study in vivo the antitumor activity of transferred peritoneal exudate cells (PEC) from Corynebacterium parvum-treated C3Hf/Bu mice. Inhibition of tumor growth was demonstrated when fibrosarcoma cells admixed with C. parvum-stimulated PEC (CP-PEC) were transplanted either ip or sc; the level of effect increased with the ratio of effector to target cells. In ip transfer experiments, the activity of transferred CP-PEC was substantially reduced when recipient mice were pretreated with 600 rads whole-body irradiation. Reconstitution of whole-body-irradiated (WBI) mice with mixed normal spleen and lymph node cells, spleen cells alone, or normal bone marrow cells did not restore the antitumor activity of transferred CP-PEC. Indeed, mice reconstituted ip showed a poorer transferred antitumor response than unreconstituted WBI mice, Inhibition of CP-PEC activity was also observed in sc transfer experiments when normal PEC, spleen cells, or separated T-cells were admixed with tumor cells and CP-PEC. However, admixed fetal fibroblasts, radiation-killed tumor cells, washed erythrocytes, or inert plastic microspheres also inhibited the action of CP-PEC to an equal or greater extent, which indicated that the inhibitory effect did not depend specifically on the presence of lymphoid elements, Possible reasons for the markedly reduced antitumor activity of CP-PEC transferred into WBI recipients were considered in the light of the experimental results.
Case 3-1995
Authors: J.A. Fishman, A.R. Mattia
Journal: New England Journal of Medicine (1995)

Presentation of CaseA 29-year-old man was admitted to the hospital because of the acquired immunodeficiency syndrome (AIDS) and multiple splenic abscesses.The patient was homosexual and had been found to have AIDS two and a half years earlier; at that time the CD4 cell count was 173 per cubic millimeter. He had a positive serologic test for cytomegalovirus antibodies and negative serologic tests for syphilis, toxoplasma, and hepatitis B surface antigen and antibody; he was anergic to tuberculin. An episode of Salmonella choleraesuis bacteremia occurred 16 months before admission, and the patient was treated for 6 months with ciprofloxacin. . . .
P250 Correlation between Attendance Rates and Socioeconomic Deprivation at a Difficult Asthma Clinic in a Large Inner City Teaching Hospital
Authors: C Dillon, S Mault, B McDonough, M Ahmad, Y Narang, H Burhan, NER Beveridge
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Missed clinic appointments are a huge financial burden on the NHS, with an average of 6.9 million outpatient appointments being missed each year.<sup>1</sup> The difficult asthma clinic at our inner city hospital is no exception to this trend. Many factors are likely to contribute to missed appointments, which can be summarised in with in socioeconomic deprivation indices. We wanted to confirm whether there is an association between missed appointments and socio-economic deprivation. We hypothesised that non-attenders lived in areas with worse deprivation scores. <h3>Method</h3> We compared deprivation scores of English postcodes of clinic attenders and non-attenders of a ‘difficult asthma clinic’ between 2011–2014 inclusive. Indices of multiple deprivation scores were using census related data and Townsend Index via UK data service ©University of Essex and University of Manchester. This provides a validated, relative measure of deprivation across small localities in England to enable comparison. A higher score represents an area with worse socio-economic deprivation, maximum score = 100. Mann-Whitney two-tailed tests to compare non-paired non-parametric data were performed in Prism version 6 (GraphPad). <h3>Results</h3> The median deprivation score of postcodes of non-attenders (n = 458) was 60.69, whereas for attenders it was 51.12 (n = 505), with a p value of &lt;0.0001. <h3>Conclusion</h3> These results strongly suggest socioeconomic deprivation has a negative impact on attendance rates at this specific clinic. Challenging socio-economic conditions are detrimental to healthcare in multiple ways and it can be difficult for patients to access resources needed to manage their healthcare need effectively. However, we hope to assess the effect of deprivation in a control medical clinic to explore the specificity of this result to asthma clinics. It would also be valuable to investigate if these DNA rates are reflected in community clinics, as this may be an alternative way to deliver this service in order to reduce overall DNA rates in deprived areas. <h3>Reference</h3> 1 http://www.england.nhs.uk/2014/03/05/missed-appts/
Leukemoid Blood Reactions
Authors: Schuyler V. Hilts, Christopher C. Shaw
Journal: New England Journal of Medicine (1953)

THE apparent coincidence of leukemia and various infections, principally tuberculosis, was noted by various observers, mostly in the German literature, as early as 1900.1 However, the first careful consideration of leukemia-like blood pictures as nonmalignant entities was in 1926 by Krumbhaar,2 who coined the term "leukemoid" to describe them. Since bone-marrow biopsy as a diagnostic aid was not in general use at that time, coincidental leukemia cannot positively be ruled out in some of his cases. Indeed, it was found that many of the cases reported, including some widely cited by other authors, may have been truly leukemic, since some . . .
P49 The stromal compartment of hepatocellular carcinoma promotes the local differentiation of tolerogenic dendritic cells
Authors: A Bhatt, S M Curbishley, E L Haughton, C J Weston, M Blahova, D H Adams
Journal: Gut (2010)

Introduction  Hepatocellular carcinoma (HCC) stimulates an immune response but this fails to destroy the tumour which contains “stunned” effector T-cells and regulatory T cells (Tregs) that suppress antigen-specific responses. The number of Tregs in the tumour predicts survival in patients undergoing resection. The underlying mechanisms that suppress anti-tumour immunity are unknown. Because dendritic cells (DC) are critical for the induction and maintenance of immune activation we studied the effect of the tumour microenvironment on DC function in patients with HCC. We hypothesise that the tumour microenvironment (TM) modifies DC differentiation resulting in the suppression of anti-tumour immunity.  Aim  In order to test this hypothesis we modelled the TM in vitro and studied its effect on the differentiation and function of DCs.  Method  DCs isolated from HCC tumour cores and uninvolved human liver tissue were compared with human monocyte-derived DCs (MoDC) matured in tissue conditioned media (CM). DC function was studied in T cell activation assays and the effect of tumour on DC function modelled by co-culturing with either tumour tissue or tumour-derived fibroblasts.  Results  Tumour-derived DCs had a tolerogenic phenotype (MHCIIlowCD86low) compared with DC isolated from matched uninvolved liver. This phenotype was recapitulated in vitro by culturing MoDCs in HCC CM after which levels of MHC II and CD86 were significantly lower than on MoDCs matured in matched non-tumour liver CM (p=0.001). Tumour-conditioned MoDCs induced significantly less naive T cell proliferation compared with MoDC matured in CM from uninvolved or inflamed liver tissue. Furthermore tumour-conditioned DCs generated significantly more CD4+CD25+FOXP3+ Tregs (p=0.01) and IL10producing T-cells (p=0.01). To determine the cell type responsible for this effect naive MoDCs were co-cultured with fibroblasts (-smooth muscle actin+vimentin+CD90+) isolated from either tumour cores or uninvolved liver. DCs conditioned by tumour fibroblasts developed a tolerogenic phenotype (MHCIIlowCD86low) and the ability to induce Tregs. Culturing MoDCs in tumour stroma CM had a similar effect implicating soluble factors. Part of this effect was IL-6-dependent because depletion of IL-6 from tumour-fibroblast CM abolished the ability to generate tolerogenic DC.  Conclusion  Tumour associated fibroblasts in HCC contribute to an IL-6-rich TM that drives differentiation of tolerogenic DCs. These DCs generate immunosuppressive Tregs and IL-10 secreting T-cells which inhibit anti-tumour immunity. Inhibition of IL-6 or downstream STAT-3 signalling could prevent tumour-associated immunosuppression and hence be an important immunotherapeutic strategy in HCC.
Recognition of Acute Myocarditis Masquerading as Acute Myocardial Infarction
Authors: Jagat Narula, Ban An Khaw, G. William Dec, Igor F. Palacios, James F. Southern, John T. Fallon, H. William Strauss, Edgar Haber, Tsunehiro Yasuda
Journal: New England Journal of Medicine (1993)

Myocarditis occasionally masquerades as acute myocardial infarction because patients may present with severe chest pain, electrocardiographic changes, and elevated serum levels of creatine kinase. In patients with normal coronary arteries who presumably died of acute myocardial infarction, myocarditis has been reported as an incidental abnormality at autopsy1–4. Although there have been anecdotal clinical reports of myocarditis mimicking myocardial infarction in patients with normal coronary arteries, this association has almost always relied on a demonstration of diffuse electrocardiographic abnormalities or a preceding viral illness in young patients with few coronary risk factors5–7. In most cases no definitive . . .
FRI0214 Disease Activity and Risk of Cardiovascular Disease in Patients with Ankylosing Spondylitis with High and Low Body Mass Index:
Authors: I.J. Berg, A.G. Semb, D. van der Heijde, T.K. Kvien, H. Dagfinrud, J. Hisdal, S.A. Provan
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Patients with ankylosing spondylitis (AS) have increased risk of cardiovascular disease (CVD), but the mediators of this increased risk are not known. Obesity is related to increased risk of CVD in the general population. Adipose tissue is an endocrine organ secreting pro-inflammatory cytokines which may be relevant both to the pathology of inflammatory diseases and CVD. <h3>Objectives</h3> To explore the impact of body mass index (BMI) on disease activity and CVD risk in AS. <h3>Methods</h3> Cross-sectional study of 159 AS patients diagnosed according to the mNY criteria. Data-collection included questionnaires, blood samples and clinical examination. Carotid intima-media thickness (c-IMT) was measured by ultrasound. Height (m) and weight (kg) were measured and BMI was calculated (kg/m<sup>2</sup>).The patients were categorized according to the BMI, with cut-off value between normal weight and over weight: BMI&lt;25 kg/m<sup>2</sup> (BMI-low) and BMI≥25kg/m<sup>2</sup> (BMI-high). We compared markers of disease activity and CVD risk factors between the BMI-low and BMI-high group in linear regression models with adjustments for age, gender and smoking habits. Additional adjustments for use of non-steroidal anti-inflammatory drugs (NSAIDs) were also performed. <h3>Results</h3> The AS patients had comparable age (years) in both groups (BMI-low vs. BMI-high), mean (SD) 50.5 years (13.2) vs. 50.5 years (11.3), respectively, but the BMI-low differed from the BMI-high regarding: male gender, 53% vs. 71%, p=0.02; CRP (mg/L), median (IQR) 2 (1-5) vs. 5 (2-13) p=0.003; use of NSAIDs, 56% vs. 74%, p=0.01. In regression analyses the BMI-high group had higher ASDAS and BASDAI than the BMI-low group. High BMI was associated with lower high-density lipoprotein (HDL), higher triglycerides, total cholesterol/HDL ratio, systolic and diastolic blood pressure as well as c-IMT (table). Additional adjustment for use of NSAIDs did not alter results. <h3>Conclusions</h3> AS patients with high BMI had worse disease activity, increased traditional CVD risk factors and increased c-IMT. Thus, obesity can be a common factor related to both disease activity and increased CVD risk and should be addressed in future observational studies in AS and considered as a potential confounding variable in future randomized controlled clinical trials. <h3>Disclosure of Interest</h3> None declared
Expression of Corticosteroid Regulated Genes By Peripheral Blood Mononuclear Cells (PBMCs) in Children from the NIH/Niaid Sponsored Asthma Phenotypes in the Inner City (APIC) Study after One Year of Guidelines-Based Therapy
Authors: Elena Goleva, Leisa P. Jackson, Baomei Shao, Zheng Hu, Michelle A. Gill, Denise C. Babineau, Andrew H. Liu, Donald Y.M. Leung
Journal: Journal of Allergy and Clinical Immunology (2016)
Growth Charting of Brain Connectivity Networks and the Identification of Attention Impairment in Youth
Authors: Daniel Kessler, Michael Angstadt, Chandra Sripada
Journal: JAMA Psychiatry (2016)

Intrinsic connectivity networks (ICNs), important units of brain functional organization, demonstrate substantial maturation during youth. In addition, interrelationships between ICNs have been reliably implicated in attention performance. It is unknown whether alterations in ICN maturational profiles can reliably detect impaired attention functioning in youth.To use a network growth charting approach to investigate the association between alterations in ICN maturation and attention performance.Data were obtained from the publicly available Philadelphia Neurodevelopmental Cohort, a prospective, population-based sample of 9498 youths who underwent genomic testing, neurocognitive assessment, and neuroimaging. Data collection was conducted at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011, and data analysis was conducted between February 1, 2015, and January 15, 2016.Statistical associations between deviations from normative network growth were assessed as well as 2 main outcome measures: accuracy during the Penn Continuous Performance Test and diagnosis with attention-deficit/hyperactivity disorder.Of the 9498 individuals identified, 1000 youths aged 8 to 22 years underwent brain imaging. A sample of 519 youths who met quality control criteria entered analysis, of whom 25 (4.8%) met criteria for attention-deficit/hyperactivity disorder. The mean (SD) age of the youth was 15.7 (3.1) years, and 223 (43.0%) were male. Participants' patterns of deviations from normative maturational trajectories were indicative of sustained attention functioning (R2 = 24%; F6,512 = 26.89; P < 2.2 × 10-16). Moreover, these patterns were found to be a reliable biomarker of severe attention impairment (peak receiver operating characteristic curve measured by area under the curve, 79.3%). In particular, a down-shifted pattern of ICN maturation (shallow maturation), rather than a right-shifted pattern (lagged maturation), was implicated in reduced attention performance (Akaike information criterion relative likelihood, 3.22 × 1026). Finally, parallel associations between ICN dysmaturation and diagnosis of attention-deficit/hyperactivity disorder were identified.Growth charting methods are widely used to assess the development of physical or other biometric characteristics, such as weight and head circumference. To date, this is the first demonstration that this method can be extended to development of functional brain networks to identify clinically relevant conditions, such as dysfunction of sustained attention.
Ebstein's Disease
Authors: R. M. McCredie, Celia Oakley, Earle B. Mahoney, Paul N. Yu
Journal: New England Journal of Medicine (1962)

EBSTEIN'S disease,1 a rare congenital anomaly that accounts for less than 1 per cent of all congenital heart disease, is characterized by malformation and downward displacement of the tricuspid valve. The cusps are grossly malformed and present a curious basketlike arrangement. Although the anterior cusp retains some attachment to the atrioventricular ring, the rest of the valve is attached lower down to the walls of the right ventricle.2 The anatomic right ventricle is thus divided into two chambers: one proximal to the valve, which is grossly dilated and thin walled and continuous with the right atrium; and a distal chamber . . .
Evaluation of age and CMV status as prognostic factors in match-unrelated donor (MUD) stem cell transplant (SCT).
Authors: C. Veeder, J. J. Maciejewski, S. Nathan, E. S. Rich, S. Davies, C. Havey, H. C. Fung
Journal: Journal of Clinical Oncology (2010)

e17002 Background: Allogeneic stem cell transplantation (SCT) is an effective treatment for patients with various hematologic malignancies and life-threatening blood disorders, although the utility of this treatment modality is severely limited by the availability of donors. Approximately 30% of patients will have an HLA identical sibling, while it is necessary to identity a suitable unrelated donor through National Marrow Donor Registry for the rest of such individuals. Here, we review a single institution experience in unrelated donor allogeneic SCT and evaluate various prognostic factors that might predict transplant outcomes. Methods: A retrospective chart review was performed for all patients who have undergone an unrelated donor allogeneic SCT at Rush University Medical Center between 2001-2009. We evaluated various donor/recipient characteristics, toxicities, and survival. Cytomegalovirus serologic status, sex mismatch, and dissimilarity score were correlated with overall survival and acute and/or chronic graft-versus-host disease (GVHD). Results: During the study period 72 patients underwent MUD-SCT at our institution and most of the patients had a hematologic malignancy. The one-year survival rate was 70% for patient less than 45 years old versus 39% for patients 45 or older. 30% of patients less than 45 years old had a max acute GVHD of grade 2-4 versus 48% for those older than 45. Of those that had an acute GVHD of grade 3-4, 2/7 were less than 45, while 5/7 were 45 years or older. All patients with grade 3-4 acute GVHD died within 1-year posttransplant. With an HLA-match of 10/10, 47% of patients survived versus a 32% survival rate when there were 1-3 mismatched alleles. When both the donor and recipient were CMV positive the survival rate was 25% and when both were CMV negative the survival rate was 64%. Sex matched transplants had a 46% survival rate versus 50% for sex mis- matched transplants. Conclusions: We conclude that age greater than 45 predicted for inferior transplant outcomes though approximately one-third of such patients can still benefit from a MUD-SCT. CMV negativity for both donor and recipient was associated with favorable outcome. No significant financial relationships to disclose.
Improving the CAC Score by Addition of Regional Measures of Calcium Distribution
Authors: Michael J. Blaha, Matthew J. Budoff, Rajesh Tota-Maharaj, Zeina A. Dardari, Nathan D. Wong, Richard A. Kronmal, John Eng, Wendy S. Post, Roger S. Blumenthal, Khurram Nasir
Journal: JACC. Cardiovascular imaging (2016)