tbuckley/cabot-search huggingface dataset:
Alternative suppression strategy for human breast cancer invasion and metastasis: a potential for a new differentiation therapy.
Authors: AS Sultan, ZA Sherif
Journal: Cancer Research (2009)

Abstract Abstract #2059 Poor prognosis of human breast cancer is associated with a high potential of cancer cells invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. We have recently uncovered novel evidence that signal transducers and activators of transcription 5a (Stat5a) and its Janus tyrosine kinase, (Jak2), suppress invasion and promote human breast cancer cells differentiation through inhibition of epithelial-to-mesenchymal dedifferentiation.&amp;#x2028; However, the precise mechanism of Jak2/Stat5a role in human breast cancer is still under investigation.&amp;#x2028; In this study, we have further critically taken advantage of the combination of Jak2/Stat5a genes expression, HDAC inhibitors, and Mistletoe (Viscum album) plant extracts as an alternative way to suppress breast cancer progression by reversing the mesenchymal phenotype, and restoring homotypic adhesion, and in turn induce tumor differentiation in vitro and in vivo. We have expanded our investigation to involve a highly invasive breast cancer cell line, MDA-231, in addition to BT-20 and T-47D human breast cancer cells that display different phenotypic and differentiation patterns ranging from poor to high differentiation. Cells were pretreated with or without different HDAC inhibitors, and/or Mistletoe (Viscum album) plant extracts, and then either mock infected or infected with adenovirus carrying Wild type (Wt-Jak2), Wt-Stat5a, Dominant negative (Dn-Stat5), or a combination of Wt-Jak2 and Wt-Stat5a.&amp;#x2028; Using three-dimensional (3D) Matrigel model system in vitro, the pretreatment with HDAC inhibitors and/or Mistletoe (Viscum album) plant extracts synergized with co-expression of Wt-Jak2/Stat5a genes to promote epithelial differentiation by reversing the mesenchymal phenotype morphology, inducing homotypic adhesion, and inhibiting cell motility and invasiveness.&amp;#x2028; We have also established a xenograft tumor model of MDA-231 cells in nude mice for in vivo studies. After 4 week, the growth of MDA-231 tumors that co-expressing Wt-Jak2/Stat5a was inhibited by 47.90% compared to the mock group (t=2.821, P&amp;lt;0.05) and by 52.86% compared to the tumors expressing Dn-Stat5 group (t=2.394, P&amp;lt;0.05). Furthermore, the pretreatment with HDAC inhibitors and/or Mistletoe (Viscum album) plant extracts enhanced significantly the growth inhibition of MDA-231 xenografted tumors expressing Wt-Jak2/Stat5a compared to the tumors expressing Wt-Stat5a or Wt-Jak2 alone.&amp;#x2028; Collectively, the observations support a novel role of Jak2/Stat5a genes as a new tool to restore lost differentiation of human breast cancer through inhibiting EMT that could lead to new therapeutic strategies to reverse cancer progression-related changes and introduce alternative cancer treatments in addition to standard chemotherapy and radiation treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2059.
Abstract 3191: Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating hedgehog signaling
Authors: Fuchuan E. Li, Wen Shi, Mariana Capurro, Jorge Filmus
Journal: Cancer Research (2010)

Abstract Glypican-5 is one of the six members of the glypican family. It has been previously reported that glypican-5 stimulates the proliferation of rhabdomyosarcoma cells. In this study we show that this stimulatory activity of glypican-5 is due to its ability to promote Hedgehog signaling. We have previously shown that glypican-3, another member of the glypican family, inhibits Hedgehog signaling by competing with Patched for Hedgehog binding. Furthermore, we showed that glypican-3 binds to Hedgehog through its core protein but not to Patched. Here we demonstrate that glypican-5 can increase the binding of Sonic Hedgehog to Patched. We also show that glypican-5 can bind to both Hedgehog and Patched through its glycosaminoglycan chains. Interestingly, we found that the heparan sulfate chains of glypican-5 display a significantly higher degree of sulfation than those from glypican-3. In addition, we show that glypican-5 interacts with Hedgehog with a lower affinity than glypican-3. Based on these results, we propose that glypican-5 stimulates Hedgehog signaling by facilitating/stabilizing the interaction between Hedgehog and Patched. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 3191.
Lassa Fever: Response to an Imported Case
Authors: Ronald M. Zweighaft, David W. Fraser, Michael A. W. Hattwick, William G. Winkler, Wilbert C. Jordan, Miriam Alter, Martin Wolfe, Herta Wulff, Karl M. Johnson
Journal: New England Journal of Medicine (1977)

In February, 1976, a Peace Corps worker returned to the United States from Sierra Leone with an undiagnosed illness later recognized as Lassa fever. To assess the risk of transmission and to contain a potential outbreak, we identified 552 contacts as having had exposure to the patient before the start of strict isolation procedures, and maintained intensive surveillance on these contacts for 21 days. At the end of the surveillance period, no illness had developed in contacts. One month later, a serologic survey among 29 of the contacts judged to be at high risk gave no evidence of infection. In response to the importation of this communicable and highly fatal disease, procedures for the isolation of the patient, the identification, surveillance and management of contacts and the handling of laboratory specimens were developed and implemented. These procedures could be adapted to future introductions of highly contagious diseases.
Abstract 4048: Increased expression of PACS-1 in cervical cancer is associated with loss of microRNA449a
Authors: Mysore S. Veena, Santanu Raychaudhuri, Huihong You, Saroj K. Basak, Kayvan Zainabadi, Gary Thomas, Eri Srivatsan
Journal: Cancer Research (2010)

Abstract Cervical cancer is one of the leading causes of female death world wide with approximately 50,000 deaths per year. We identified a 300 kb deletion of chromosome 11q13 in cervical cancer and mapped eleven genes to this region. Of these, phosphofurin acidic cluster sorting −1 (PACS-1) gene encodes a multi-functional sorting protein involved in secretory pathway membrane traffic. Expression studies showed the presence of an abnormal PACS-1 transcript in tumorigenic cell lines. Protein expression studies in paired normal and cervical tumors showed over-expression of PACS-1 protein in tumor specimens. RT-PCR indicated that protein over-expression was related to over-expression at the RNA level. These findings together with the absence of detectable mutations in PACS-1 exons in HeLa or SiHa cervical carcinoma cell lines raised the possibility that dysregulation of a microRNA (miRNA) may alter PACS-1 expression in cervical cancer. Consistent with this possibility, a UCSC genome database search showed the presence of binding sites for miRNA449a in the 3′ UTR (untranslated region) of the PACS-1 RNA transcript. Co-transfection of PACS-1 3′UTR luciferase reporter with miRNA449a resulted in reduced expression of luciferase. Expression of miR449a in HeLa and SiHa cells led to reduced expression of PACS-1 and increased expression of p53 and p21 proteins. FACS analysis of HeLa cells transfected with miR449a showed a reduction in S phase indicating the growth suppressive effect of miR449a. These results indicate that miR449a regulates PACS-1 expression and loss of miR449a expression leads to over-expression of PACS-1. This in turn seems to result in the destabilization of p53 in cervical cancer. Our findings suggest PACS-1 plays a role in cervical cancer development and its expression is regulated post-transcriptionally by miRNA449a. 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 4048.
Relative Risk Factors for Cardiac Erosion Following Transcatheter Closure of Atrial Septal Defects
Authors: Doff B. McElhinney, Michael D. Quartermain, Damien Kenny, Ernerio Alboliras, Zahid Amin
Journal: Circulation (2016)

Transcatheter closure of secundum atrial septal defects (ASD) using the Amplatzer septal occluder is generally safe and effective, but erosion into the pericardial space or aorta has been described. Although the absolute risk of this complication is low, there has been no assessment of relative risk factors.All erosions reported to St. Jude Medical after ASD closure with an Amplatzer septal occluder (cases) were compared with controls (matched 2:1) who underwent ASD closure but did not develop an erosion. A total of 125 erosions were reported between 2002 and 2014, including 95 with an available echocardiogram. The median duration from implant to erosion was 14 days, but was >1 year in 16 patients. Nine patients (all age ≥17 years) who died were more likely to have an oversized device, and to have erosion into the aorta, than survivors. Aortic or superior vena cava rim deficiencies were more common in cases than in controls. In addition, larger balloon-sized ASD diameter, Amplatzer septal occluder device size, and device size-ASD diameter difference, and smaller weight:device size ratio were associated with erosion. On multivariable analysis, deficiency of any rim, device >5 mm larger than ASD diameter, and weight:device size ratio were associated with erosion.In addition to aortic rim deficiency, which was almost universal among erosion cases, there were several relative risk factors for erosion after ASD closure with the Amplatzer septal occluder device. To understand the mechanisms of and absolute risk factors for this uncommon but serious complication, an adequately powered prospective study with thorough echocardiographic evaluation will be critical.
Increased Resistance to Penicillin of Pneumococci Isolated from Man
Authors: David Hansman, Heatherbell Glasgow, John Sturt, Lorraine Devitt, Robert Douglas
Journal: New England Journal of Medicine (1971)

Strains of Diplococcus pneumoniae relatively insensitive to penicillin were isolated from an aboriginal child in Australia and from 15 New Guineans. The concentration of penicillin required to inhibit growth was 25 times that which inhibited sensitive pneumococci. These pneumococci were also partially resistant to cephalosporin antibiotics. All the relatively insensitive pneumococci from New Guinea were identified as Type 4, suggesting that transmission of the partially resistant strain had occurred. The isolations were made from persons who lived in remote areas where penicillin had frequently been used.
Abstract 1167: Fixation does not affect the integrity of microRNAs in archival colorectal cancer specimens over a period of 20 years
Authors: Liselle C. Bovell, ChandraKumar Shanmugam, Venkat Katkoori, Chura Salih, William E. Grizzle, Upender Manne
Journal: Cancer Research (2011)

Abstract Background: MicroRNAs (miRNAs) have potential prognostic and therapeutic value in human malignancies, including colorectal cancer (CRC). Many human tumor tissues are available as formalin-fixed paraffin-embedded (FFPE) specimens, which are an excellent source for biomarker discovery. However, the stability of miRNAs and the reliability of measurements of miRNA expression in archival samples stored for long periods of time (&amp;gt; 20 years) are not known. Therefore, we evaluated the stability and expression levels of miRNAs in FFPE CRC specimens and compared their expression levels to those in CRC cell lines. Methods: A panel of seven miRNAs (RNU6B, miR-20a, miR-21, miR-106a, miR-181b, miR-203, and miR-324-5p) in 219 CRC archival tissue samples, stored for 6 to 28 years (1982 through 2004) in a dark, cool place, and 11 CRC cell lines (LoVo, HCT116, HCT116 (p53-/-), RKO, LS174T, CaCo-2, Colo205, SW480, WiDr, HCT-15, and DLD-1) were evaluated by the use of TaqMan® microRNA assays and by quantitative real-time polymerase chain reactions. In CRCs, these miRNAs, excluding RNU6B (an endogenous reference molecule), are candidate prognostic or predictive biomarkers. All assay reagents used were from Applied Biosystems Inc., (Carlsbad, CA). From each block, tissue sections, 10-microns thick, were used for extraction of miRNAs. miRNA expression was measured as threshold cycle (Ct) values. Triplicate reactions were averaged for each miRNA, and the raw Ct values were determined. The Kruskal-Wallis one-way analysis of variance was employed to analyze the miRNA expression difference among archived samples from different years. Correlation coefficient analysis was performed to compare the expression levels of miRNA in archival tissues and cell lines. Results: In both CRC archival tissues and cell lines, the median Ct values of all miRNAs ranged from 19 to 32. All seven miRNAs were stable in CRC tissues stored for up to 28 years; their expression levels were similar across all ages of blocks. (Kruskall-Wallis P values for all 7 miRNAs ranged from 0.627 to 1.000.) There was good correlation between the levels of expression of all seven miRNAs in FFPE tissues and in the CRC cell lines (correlation coefficient R2 range, 0.784 to 0.937). Conclusions: Since miRNAs are stable in archival CRC samples stored for over 20 years, FFPE samples can be used to evaluate miRNAs as biomarkers. These studies were supported by grants 2U54-CA118948-03, R01-CA98932, and R03-CA139629 from the NCI/NIH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1167. doi:10.1158/1538-7445.AM2011-1167
THE IMPACT OF INTRODUCING A 24/7 EMERGENCY GASTROINTESTINAL (GI) BLEEDS SERVICE ON REDUCING HOSPITAL STAY AND MORTALITY IN A DISTRICT GENERAL HOSPITAL
Authors: Z U Rahman, S Ahmed, S U Rehman, A Dixon
Journal: Gut (2013)

<h3>Introduction</h3> The impact of introducing a 24/7 emergency gastrointestinal (GI) bleeds service on reducing hospital stay and mortality in a District General Hospital. <h3>Aims/Background</h3> Upper GI bleed remains the commonest gastrointestinal emergency with a significantly high hospital mortality and prolonged hospital stay.<sup>1</sup> The aim of this study was to audit any difference of the above parameters after the introduction of GI bleed rota in our trust. <h3>Method</h3> The data was collected from patient records and endoscopy database. Rockall score was used Standard statistical methods were used for analysing and Comparisons were made with an audit undertaken in 2005. <h3>Results</h3> The re audit undertaken was conducted and compared to a previous one which was done in 2005, after introducing local upper GI bleed guidelines and a 24/7 GI bleed rota. A total of 107 patients (including both in- and outpatients) were referred for upper Gastrointestinal endoscopy with suspected upper GI bleed from 1st Jan to 30th June 2012. A sample of 39 patients were randomly (every third patient) included in the audit with 19 females and 20 males. The mean age was 69.6yrs (39–93).The time interval from presentation to therapeutic endoscopy was 35.35 hrs as opposed to 2.82 days according to 2005 audit data. Amongst the endoscopy findings 12.82 % (5/39) patients had Gastrooesophageal varices versus no banding in 2005 audit data; there was no significant difference among other aetiologies in both audit samples. Thirty day mortality was 7.7 % (3/39) as compared to 13.33 % (4/30) in 2005.The length of hospital stay was found to be 10.7 days as compared to 12.32 days (2005). <h3>Conclusion</h3> (1) The mortality was reduced as the time delay to therapeutic endoscopy reduced. (2) The hospital stay has been shortened by a couple of days in this study sample. The estimated cost of 24/7 GI bleed rota is 15000 pounds per annum which can potentially save significant amount of funding by reducing hospital stay i.e. An investment worth spending on. (3) The incidence of variceal bleeding has increased significantly over the years.
AB0762 Clinical Associations of the IL-17A, IL-17F and Nfkb-1 Gene Polymorphisms in Patients with Rheumatoid and Psoriatic Arthritis
Authors: R. Sokolik, J. Świerkot, K. Gębura, B. Wysoczańska, M. Bielańska, L. Korman, P. Wiland, K. Bogunia-Kubik
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The pro-inflammatory cytokines IL-17A and IL-17F, primarily produced by Th17 cells, has been shown to be involved in all stages of the autoimmune and inflammatory diseases [1]. Th17 cells are thought to play an important role in rheumatoid (RA) and psoriatic arthritis (PsA) [2]. <h3>Objectives</h3> The present study aimed to determine the association between their polymorphic variants with possible involvement in disease susceptibility and effect on disease progression in patients with PsA and RA susceptibility, progression and response to therapy with TNF-alpha inhibitors. <h3>Methods</h3> Eighty-nine RA and 54 PsA patients and 126 healthy individuals were investigated and genotyped for the <i>IL-17A</i> (rs2275913; G-197A), <i>IL-17F</i> (rs763780; A7488G; His161Arg) and transcription nuclear factor <i>NFkB-1</i> (rs28362491; -94 ins/del ATTG) alleles. <h3>Results</h3> Female RA patients carrying the <i>IL-17A</i> wild type genotype more frequently presented with radiographic changes grade 4 (Steinbrocker) (8/24 vs. 6/47, p=0.058) and were characterized by more active disease after 3 months of therapy with the TNF inhibitors (12/23 vs. 15/45, p=0.040). The presence of the <i>IL-17F</i> minor (<i>G</i>) variant (OR=3.97, p&lt;0.001) and its homozygosity (OR=29.62, p&lt;0.001) was more frequent among RA patients than healthy individuals. The <i>NFkB1 del</i> genotype was more frequently observed in patients with PsA onset over 40 year of age (16/20 vs. 8/17, p=0.047). PsA patients lacking this <i>NFkB1 del/del</i> genotype (<i>ins</i> positive cases) more frequently presented with severe disease (PASI &gt;10, BSA &gt;10, more than five swollen and tender joints) and subjected to anti-TNF-alpha therapy (20/21 vs. 12/18, p=0.035). <h3>Conclusions</h3> These results suggest that the <i>IL-17A</i> and <i>IL-17F</i> polymoprhisms play a significant role in RA while <i>NFkB-1</i> variants seem to affect PsA. <h3>References</h3> Miossec P, Kolls JK. Targeting IL-17 and TH 17 cells in chronic inflammation. Nat Rev Drug Discov 2012; 11:763:776 Shen H., Goodal JC, Hill Ga ston JS. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spodylitis and rheumatoid arthritis. Arthritis Rheum 2009; 60:1647-1656. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5856
Abstract 4260: Histone deacetylase 11 (HDAC11) as a novel therapeutic target in the regulation of myeloid-derived suppressor cell (MDSC)
Authors: Eva Sahakian, John Powers, Jennifer Rock-Klotz, Adriani Marsilio, Karune Woan, Oscar Merino, Ajaypal Gill, Susan Deng, Fengdong Cheng, Alejandro Villagra, Noreen Luekette, Edward Seto, Ivan Borrello, Eduardo Sotomayor, Javier I. Pinilla
Journal: Cancer Research (2012)

Abstract The physiological role of this HDAC11, the newest member of the HDAC family was mainly unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro. To better elucidate the role of HDAC11 in these cells, we have utilized HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression /transcriptional activity in immune cells in vivo. Immature myeloid cells (IMCs) differentiate into macrophages, dendritic cells, and neutrophils and are also considered to be precursors of MDSCs in tumor-bearing hosts. Here, we show for the first time that HDAC11 plays an important role in this process. First, IMCs from the bone marrow and spleen of TgHDAC11-eGFP mice display high expression of eGFP indicative of HDAC11 transcriptional activation in these cells in the steady state. Subcutaneous injection of EL4 tumor cells into these mice resulted in expansion of MDSCs (identified by the expression of CD11b+/GR1+ [Ly6G and Ly6C] with variable expression of CD49d and CD115) in their lymphoid organs which was similar in extent to the expansion observed in tumor-bearing wild type (WT) mice. Of note, flow cytometric analysis revealed that expression of eGFP was significantly decreased in the myeloid compartment of tumor bearing TgHDAC11-eGFP mice, with greatest decrease in the Ly6Chigh population suggesting that the transition of IMC into MDSCs might require a decrease in HDAC11 expression. Reminiscent of our findings in the eGFP mice, studies in nontransgenic mice also demonstrated that tumor derived MDSCs display less HDAC11 mRNA expression compared to splenic MDSCs, with lowest expression of HDAC11 in the Ly6Chigh MDSCs. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our preliminary functional studies in TgHDAC11-eGFP mice which demonstrates that isolated GR1+/eGFP- cells demonstrate more suppressive phenotype than that of GR1+/eGFP+ cells, in the presence of tumor challenge. Taken together, these results suggest that HDAC11 plays a regulatory role in the expansion and function of MDSCs in vivo. A better understanding of this previously unknown role of HDAC11 in MDSC biology might lead to targeted epigenetic therapies to influence the suppressive abilities of these cells and augment the efficacy of immunotherapeutic approaches against malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4260. doi:1538-7445.AM2012-4260