tbuckley/cabot-search huggingface dataset:
Abstract 2187: RNAi- and U1 small nuclear interference (U1i)-mediated gene knockdown reveals the functional relevance of Pim-1 kinase in colon carcinoma and glioblastoma.
Authors: Ulrike Weirauch, Maren Thomas, Arnold Grünweller, Roland K. Hartmann, Achim M. Aigner
Journal: Cancer Research (2013)

Abstract Pim-1 is a constitutively active serine/threonine kinase overexpressed in various tumors. Its role as proto-oncogene is based on several Pim-1 target proteins involved in pivotal cellular processes, and Pim-1 overexpression has been linked to poor prognosis. RNAi-based knockdown approaches were used to inhibit Pim-1 in colon carcinoma cells. We demonstrate anti-proliferative, pro-apoptotic and overall antitumor effects of Pim-1 inhibition. The analysis of the molecular effects of Pim-1 inhibition reveals a complex regulatory network, with therapeutic Pim-1 repression leading to major changes in oncogenic signal transduction with regard to p21Cip1/WAF1, STAT3, JNK, c-Myc and survivin, and in the levels of apoptosis-related proteins Puma, Bax and Bcl-xL. Furthermore, Pim-1 knockdown sensitizes tumor cells towards 5-FU treatment, thereby antagonizing a 5-FU-triggered Pim-1 upregulation. This effect is mediated through decreased miR-15b levels, and our studies identify miR-15b and miR-33a to regulate Pim-1. There is first evidence of Pim-1 overexpression also in glioblastoma, but the functional relevance is so far unknown. U1 small nuclear interference (U1i) has recently been described as novel gene silencing mechanism. It employs short oligonucleotides, so-called U1 adaptors, for specific gene knockdown. We generated Pim-1 specific U1 adaptors and demonstrate their ability to induce Pim-1 knockdown in GBM cells. U1 adaptor transfection leads to anti-proliferative and pro-apoptotic effects. To explore therapeutic in vivo applications, we complexed siRNAs or U1 adaptors with a low molecular weight polyethylenimine (PEI) that mediates protection and cellular internalization. Treatment of tumor xenograft-bearing mice with PEI/siRNA or PEI/adaptor nanoparticles exhibits antitumor effects based on the knockdown of Pim-1, thus offering novel therapeutic strategies. Conclusions: We demonstrate that Pim-1 plays a pivotal role in several tumor-relevant signalling pathways, and establish the functional relevance of Pim-1 in colon carcinoma and in glioblastoma. Our results also substantiate the RNAi-mediated Pim-1 knockdown based on polymeric PEI/siRNA nanoparticles as a promising therapeutic approach, and we show that U1i represents an alternative to RNAi for the therapeutic knockdown of pathologically upregulated genes. Citation Format: Ulrike Weirauch, Maren Thomas, Arnold Grünweller, Roland K. Hartmann, Achim M. Aigner. RNAi- and U1 small nuclear interference (U1i)-mediated gene knockdown reveals the functional relevance of Pim-1 kinase in colon carcinoma and glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2187. doi:10.1158/1538-7445.AM2013-2187
Abstract 4162: MicroRNA-34 family is increased in human colon cancer and targets Peroxisome proliferator-activated receptor γ.
Authors: Yukiharu Hiyoshi, Aaron J. Schetter, Izumi Horikawa, Hideo Baba, Curtis C. Harris
Journal: Cancer Research (2013)

Abstract Purpose: The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. The aim of this study is to elucidate the roles of miR-34 family in colon carcinogenesis. Methods: MiR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR. We examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status, KRAS mutation status, promoter methylation and Affymetrix microarray data. Ingenuity Pathway Analysis (IPA) identified transcriptional regulators that were involved with miR-34 expression. In vitro experiments were performed to identify the target gene of miR-34 family. Results: All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression which is consistent with the proposed regulation of miR-34a/b/c by TP53. KRAS mutation status was associated with increased miR-34a expression. Hypermethylation of miR-34a and miR-34b/c was found in tumors. IPA found that the activity of the tumor suppressor gene Peroxisome Proliferator-Activated Receptor γ (PPARG) was negatively associated with miR-34 expression, and in vitro experiments identified PPARG as a direct target of miR-34 family. Conclusion: miR-34 family may have important roles in colon carcinogenesis as oncogenic miRNAs by targeting PPARG. Citation Format: Yukiharu Hiyoshi, Aaron J. Schetter, Izumi Horikawa, Hideo Baba, Curtis C. Harris. MicroRNA-34 family is increased in human colon cancer and targets Peroxisome proliferator-activated receptor γ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4162. doi:10.1158/1538-7445.AM2013-4162
Gaucher's Disease
Authors: Jane F. Desforges, Ernest Beutler
Journal: New England Journal of Medicine (1991)

PHYSICIANS often regard Gaucher's disease as a rare, esoteric, untreatable disorder. Fortunately, the more severe forms of the disease are indeed quite uncommon, but milder forms of Gaucher's disease are encountered frequently, particularly in the Jewish population. Moreover, effective treatment has recently become available, and the prospects for ultimately treating this relatively common disease with the use of gene transfer are quite promising.CauseGaucher's disease is an autosomal recessive disorder caused by a deficiency of glucocerebrosidase (glucosylceramidase),1 the enzyme required for the lysosomal degradation of lipids containing covalently bound sugars (glycolipids). In its absence the extremely insoluble glucocerebroside (glucosylceramide) . . .
AB0577 Bone mineral density in patients with psoraitic arthitis-a case control study
Authors: F. C. Kreeshan, M. Bukhari
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthitis is an independant risk factor of a low bone mineral density (BMD). This is presumed to be a direct effect of rheumatoid inflammation on bone. The inflammatory process in Psoraitic arthitis (PsA) is thought to be different from that in Rheumatoid arthritis and involves more entheseal disease. Bone loss is also not a feature of the gross radiographic changes and indeed increased bone density is frequently quoted (Ivory digit). In the general population BMD in the hip is a better predictor of future osteoporotic fracture than BMD in the spine. It is not known whether there is any bone loss in PsA and where it occurs. <h3>Objectives</h3> To determine whether bone loss occurs in PsA and it’s site using a nested case control approach. <h3>Methods</h3> Patients referred to a district general hospital in the North West of England for bone mineral density assessment between June 2004 to September 2010 were studied. Patients identified as having a consultant diagnosis of Psoraitic arthritis in the database were then age and gender matched with controls who were referred and scanned with no indication for scanning. Patients with other indications for scanning other than PsA were excluded. A logistic model was then fitted to determine whether or not there was a reduction in bone density in patients with PsA compared to controls. This was performed in the spine and Hip separately. The lowest T score in either hip was used in both cases and controls. Odds ratio for the T scores were obtained in the two sites, this was adjusted for height and weight, which are apossible confounders. <h3>Results</h3> 56 patients with Psoriatic arthritis were included in the study and were matched to 56 controls. The median age was 59.5 years in both cases and controls (IQR 53.5,68 years). 31 (56%) were female in both cohorts. Median height was 165 cm (IQR 160,175 cm) in cases and 166 cm (IQR160.5, 174.5 cm) in controls. Median weight was 72.9 kg (IQR 63.4,88.4 kg) in cases and 72.7kg (IQR 63.3,85.5kg) in controls. Median T score in the spine for cases was -1.4 (IQR -1.9,-0.6) and in controls it was -0.65 (IQR -1.75,0.44). In the lowest femoral neck the median T score was -1.2 (IQR -2.0,-0.423) and in controls it was -0.5 (IQR -1.22,0.23). The odds of having a lower bone mass density in PsA was 1.68(95% CI 1.18, 2.41) in the hip, and it was 1.03 (95% CI 0.83, 1.30) in the lumber spine. After adjustment for height and weight this relationship remained. (OR 1.69 95%CI 1.17,2.46 and 1.04 95%CI 0.84,1.31 respectively). <h3>Conclusions</h3> Bone loss does occur in patients with Psoriatic arthitis compared to controls. This seems to occur only in the femoral neck. As the femoral neck is the most important predictor of bone loss in patients predisposed to fracture, this deserves further study. Mechanism(s) for bone loss in PsA need more research. <h3>Disclosure of Interest</h3> None Declared
PTU-207 Detection of dysplasia arising in Barrett's oesophagus is associated with better quality endoscopic technique: Abstract PTU-207 Table 1
Authors: J Dunn, J Ooi, F Chang, J Meenan
Journal: Gut (2012)

<h3>Introduction</h3> Barrett9s columnar lined oesophagus (CLO) is the pre-malignant lesion to oesophageal adenocarcinoma (OAC). The presence of dysplasia, when diagnosed in surveillance programmes, is an important marker of risk of progression and an indication for endoscopic therapy. Barrett9s surveillance should be undertaken with a minimum of four quadrant biopsies every 2 cm, with documentation of length of BE segment by Prague C/M criteria, yet adherence to this is variable. We aimed to assess the quality of Barrett9s surveillance and effect on dysplasia detection. <h3>Methods</h3> Prospective database of patients undergoing Barrett9s surveillance over 3 year period at tertiary referral upper GI centre. Patients with a previous diagnosis of dysplasia/OAC were excluded. Endoscopists were separated into two groups; Group A—endoscopist has newly diagnosed patient with dysplasia over study period; Group B—endoscopist has not diagnosed patient with dysplasia at any time point. Analysis was by independent t-tests for continuous variables and chi-squared tests for categorical variables. <h3>Results</h3> 395 patients with Barrett9s CLO underwent endoscopy between 2007 and 2010. Of these 23/395 were diagnosed with dysplasia/OAC by group A endoscopists (n=14) vs none in Group B (n=32). Results are shown in Abstract PTU-207 table 1. There was no significant difference in patient9s age, sex or length of Barrett9s mucosa between the two groups. There was a significant difference in adherence to Seattle protocol four quadrant biopsies every 2 cm between the two groups. The detection rate of Specialised Intestinal Metaplasia (SIM) and documentation of length of Barrett9s mucosa by Prague criteria were significantly higher in group A than group B. The use of High Resolution Endoscopy was similar between both groups. <h3>Conclusion</h3> This study demonstrates that endoscopists who detect dysplasia arising in Barrett9s CLO are more likely to undertake high quality Barrett9s surveillance as evidenced by higher rates of SIM, adherence to Seattle protocol biopsy and documentation of length of Barrett9s mucosa by Prague classification. This lends support to the argument that Barrett9s surveillance should be centralised and undertaken on dedicated lists by trained endoscopists with a specialist interest, in order to maximise dysplasia detection rates. A prospective study is warranted. <h3>Competing interests</h3> None declared.
AB0693 Is there a link between vitamin d and juvenile idiopathic arthritis?
Authors: M. Nisar, P. Cookson, F. Masood, A. Sansome, A. Ostor
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Vitamin D (Vit D) insufficiency has been implicated in a number of autoimmune diseases. Its role in the pathogenesis of juvenile idiopathic arthritis (JIA) however is unclear including its relation to disease subtype and severity. <h3>Objectives</h3> To establish a link between Vit D insufficiency and JIA <h3>Methods</h3> We undertook a retrospective cohort study of Vit D levels in patients with a diagnosis of JIA. Demographic data, JIA subtype, medication use, comorbidities, disease severity, bone profile, inflammatory markers and autoantibody status were documented. Vit D levels were then correlated in each subgroup and with the other blood parameters. We predefined Vit D insufficiency as being &lt;50 nmol/L. <h3>Results</h3> In the 37 patients where Vit D levels were available, 34 (91.9%) were females, 22 white (59.9%) and the age groups were evenly split: 0-10 (n=13), 11-20 (n=12) and &gt;21 years (n=12). The mean Vit D concentration was 49.6 nmol/L (range 13.2- 112.0 nmol/L). Seventeen patients (45.9%) had Vit D levels above 50nmol/l, 9 (24.3%) between 30 and 50 nmol/l, 10 (27.0%) between 15 and 30 nmol/l, and 1 patient (2.7%) had a serum concentration below 15 nmol/l. A trend for lower Vit D levels was seen in older patients. There were no significant differences in mean Vit D levels among various ethnicities or JIA subtypes however ESR and CRP were inversely related to Vit D concentrations. Vit D levels were significantly lower in patients who were not receiving methotrexate (MTX) (p=0.04 ) and in those receiving opioids (p=0.03). <h3>Conclusions</h3> In our cohort half of patients with JIA have low Vit D levels which are inversely related to disease activity and disease duration. JIA subsets do not appear to have a direct association with Vit D however patients not receiving MTX had lower levels of Vit D. This study suggests that Vit D plays a role in JIA however further research is required to clarify its precise influence. <h3>Disclosure of Interest</h3> None Declared
Abstract B17: Synergism between p53 and Mcl-1 in hepatocyte maturation and survival
Authors: Shih-Yen Weng, Michael Hsiao, Pei-Hsin Huang, Mi-Hua Tao, Hsin-Fang Yang-Yen, Chia-Yu Yang, Chao-Chin Li, Te-Ping Sun, Shu-Yun Tung, Jeffrey Jong-Young Yen, Ting-Fen Tsai, Chun-Ming Chen, Sung Ho Chen
Journal: Cancer Research (2011)

Abstract Mcl-1 plays an apical role in many cell survival programs. Mice without Mcl-1 die at early embryonic stage. A conditional knockout approach has thus been employed to study Mcl-1 functions in the liver. Mice without Mcl-1 in hepatocytes (Alb-Mcl-1 −/−) were viable but manifested some defects in the mature liver, including enlarged cell size, enhanced apoptosis and proliferation of liver cells. An increased level of p53 was also observed in adult Alb-Mcl-1 −/− mouse livers. We thus generated Alb-Mcl-1 −/− mice in p53-deficient background to examine whether p53 was involved in Mcl-1 deficiency-induced hepatocyte apoptosis. Loss of p53 in Alb-Mcl-1 −/− mice (DKO mice) resulted in a very high frequency of neonatal death. Further analysis revealed that such early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. On the other hand, those DKO mice that did survive to adulthood manifested much more severe liver cell damage than Alb-Mcl-1 −/−mice of the same age, suggesting that p53 is activated in Alb-Mcl-1 −/− livers to help resolve Mcl-1 deficiency-induced hepatocyte damage. Last, we demonstrated that p53 enhanced-hepatocyte survival is a cell-autonomous effect, and that such effect is mediated in part through transcriptional up-regulation of p21 Waf1/Cip1 in Alb-Mcl-1 −/− livers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B17.
S54 Polymers of Z 1-antitrypsin are associated with pulmonary infection post lung transplantation
Authors: K. Santhanakrishnan, S. Alam, J. Parmar, R. Mahadeva
Journal: Thorax (2011)

Z antitrypsin (Z-AT) polymerises in the liver and is associated with early onset emphysema. Polymers of Z-AT are not only inactivate as antiproteinases, but also act as a pro-inflammatory stimulus. We studied patients with emphysema post lung transplantation, with and without AT deficiency, to examine the relationship between polymers and the presence of infection and inflammation. Bronchoalveolar Lavage Fluid (BALF) was obtained at scheduled surveillance, and when clinically indicated to assess for infection, rejection and airway injury. BALF was assessed by ELISA and immunoblot using a monoclonal antibody to polymeric AT (ATZII). BALF cell pellets were lysed, and HLE activity was used as a measure of BALF neutrophil numbers. 16 patients post-transplant were evaluated, 6 Z-AT patients (15 samples); 9 infective tracheobronchitis, 3 airway stenosis, 1 reflux, 2 normal, and 10 M-AT patients (20 samples); 7 infective tracheobronchitis, 8 rejection, 5 normal. All samples apart from one in the Z-AT group contained polymers; median (IQR) 292 (430–40.2) ng/ml. In one patient BALF was initially negative for polymers, but subsequent samples were positive. Polymers were present in association bacterial infection, colonisation, airway injury and surveillance bronchoscopy of asymptomatic patients. Airway stenosis/inflammation and bacterial tracheobronchitis was associated with a higher amount of polymers (347.35 (SEM±57 ng/ml) than Z-AT with normal findings (142±101 ng/ml). Immunoblot confirmed the classical ladders of polymers in Z-AT group, but not in M-AT group. BALF of Z-AT group had a higher free HLE than M-AT; 139(226.5–102.75) ng/ml vs 74(105.25–46) ng/ml, respectively; p≤0.001. Free HLE in Z-AT was correlated with polymer concentrations in BALF; r<sup>2</sup>=0.63. Total neutrophil numbers were higher in Z-AT compared with M-AT; OD405, 0.57±0.07 vs 0.37±0.04, respectively; p=0.033. BALF neutrophil numbers were significantly higher in the infected Z-AT (0.54±0.1) vs infected M-AT (0.31±0.1), p=0.026. We have shown that polymers of Z-AT are present in BALF of transplanted individuals. Furthermore, this was associated with excess neutrophils, and closely correlated with free HLE. The production of polymers results in further reduction of the anti-proteinase and anti-inflammatory protection in the lung and leads to neutrophil influx. This may to predispose Z-AT individuals to exaggerated lung destruction and a worse outcome after lung transplantation.
PWE-167 Identification of Altered Keratin Level in Cancerized Colonic Fields using Isobaric Tags for Relative and Absolute Quantification (ITRAQ) for Protein Profiling
Authors: R Rosser, C E Evans, K S Chapple, B M Corfe
Journal: Gut (2013)

<h3>Introduction</h3> A cancerized field is an area of abnormal tissue in the vicinity of a cancer that macroscopically appears normal, and which may be responsible for neoplastic recurrence. Evidence from keratin-8-deficient mice suggests that it is important for colonic mucosa stability. Keratin 8 (K8) levels are also up-regulated in the immediate area around colorectal carcinomas. Moreover, the anti-colorectal cancer action of butyrate may, at least in part, be mediated by K8. Therefore we investigated levels of K8, and its association with butyrate levels, in human sporadic colorectal adenomas. <h3>Methods</h3> Patients (n = 8) with an adenoma detected on routine colonoscopy had biopsies taken from three sites (adenoma [AD], bowel wall opposite adenoma [CO] and mid-sigmoid colon [MS]). Mid-sigmoid biopsies were also taken from patients (n = 8) with no colonic pathology (N). Intermediate filaments from the biopsies were extracted and solubilised, prior to pooling according to site and exposure to high (H) or low (L) butyrate within the colonic lumen (determined via faecal sampling). K8 levels were then determined using iTRAQ. GeneBio Phenyx software and the UniProt protein knowledgebase were used for protein identification. iTRAQ results were validated using Western immunoblot analysis. <h3>Results</h3> Independent of the butyrate level, K8 was increased in pathological tissue (AD, CO and MS) when compared to non-pathological tissue (figure 1). A high butyrate environment was associated with increased K8 levels compared to low butyrate samples (figure 1). Adenoma samples from both butyrate groups demonstrated a lower molecular weight form of K8 (figure 2; red arrows). <h3>Conclusion</h3> Increased K8 may represent a response to malignant transformation to stabilise colonic mucosa. Human colonic adenomas exhibit a lower molecular weight form of K8 not seen in normal colorectal mucosa, possibly associated with the degradome. The anti-neoplastic action of butyrate may be mediated via up-regulation or altered solubility of K8. <h3>Disclosure of Interest</h3> None Declared.
Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients
Authors: Jonel Trebicka, Matthias von Heydebrand, Jennifer Lehmann, Flemming Tofteng, Troels Busk, Helle Lone Jensen, Johan Rohde, Thomas Reiberger, Christian Mortensen, Robert Schierwagen, Sabine Klein, Søren Møller, Flemming Bendtsen, Aleksander Krag
Journal: Journal of Hepatology (2016)
Case 5-2012
Authors: Oliver Freudenreich, Nesli Basgoz, Carlos Fernandez-Robles, Mykol Larvie, Joseph Misdraji
Journal: New England Journal of Medicine (2012)

A 39-year-old man with a recent diagnosis of HIV infection was admitted to this hospital with fever and bizarre, nihilistic delusions, including statements that he had died. A diagnostic procedure was performed.
Mutation in the Gene Encoding the Stimulatory G Protein of Adenylate Cyclase in Albright's Hereditary Osteodystrophy
Authors: Jennifer L. Patten, Donald R. Johns, David Valle, Charles Eil, Philip A. Gruppuso, Gary Steele, Philip M. Smallwood, Michael A. Levine
Journal: New England Journal of Medicine (1990)

Albright's hereditary osteodystrophy is an autosomal dominant disorder characterized by a short stature, brachydactyly, subcutaneous ossifications, and reduced expression or function of the α subunit of the stimulatory G protein (Gsα) of adenylate cyclase, which is necessary for the action of parathyroid and other hormones that use cyclic AMP as an intracellular second messenger.