bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation
Authors: Goulis J , Chau T N , Jordan S , Mehta A B , Watkinson A , Rolles K , Burroughs A K 
Published: June 2010

BACKGROUNDThrombocytopenia in cirrhotic patients may be due to deficient production of thrombopoietin.AIMSTo determine the relation between thrombopoietin and thrombocytopenia in cirrhotic patients before and after orthotopic liver transplantation.METHODSThrombopoietin concentrations and platelet counts were measured in 43 cirrhotic patients and 21 normal controls and serially for 14 days after transplantation in 23/43 patients.RESULTS27 of the 43 patients had thrombocytopenia (platelet count less than 120 × 109/l; group 1) whereas 16 patients had normal platelet count (group 2). Thrombopoietin concentrations were lower in group 1 than in group 2 (92.5 (20.3–286.3) v 226.6 (30.1–848.3) pg/ml, p=0.003) and normal controls (92.5 (20.3–286.3)v 158.3 (22.5–232.9) pg/ml, p=0.028). Post-transplantation thrombopoietin concentrations increased with a peak at day 5. The rise was significant in patients with low pretransplantation platelet count (89.1 (21.29–247.6) to 545.1 (66.2–2569) pg/ml; n=16, p=0.001) but not in those with normal platelet count (262.8 (30.1–848.3) to 315.1 (114–954.6) pg/ml; n=7, p=0.47). No correlation was found pretransplantation between spleen volume and platelet count (r=−0.11, p=0.6) or thrombopoietin concentrations (r=−0.04, p=0.8). However, pretransplantation thrombopoietin concentrations correlated with platelet count (r=0.47, p=0.0015), whereas an inverse correlation was found between peak thrombopoietin concentrations and nadir platelet count (r=−0.41 p=0.049) post-transplantation.CONCLUSIONSInadequate thrombopoietin production may contribute to cirrhotic thrombocytopenia. Thrombopoietin production is restored after liver transplantation leading to the resolution of thrombocytopenia.
Expression and activity of mitogen activated protein kinases in human colorectal carcinoma
Authors: Eggstein S , Franke M , Kutschka I , Manthey G , von Specht B U , Ruf G , Farthmann E H 
Published: June 2010

BACKGROUNDMitogen activated protein kinases (MAPKs) play a central role in the regulation of both cell growth and differentiation. They are involved in signal transduction of oncogenes and growth factors. The role of MAPK in colonic carcinoma is unknown.AIMSTo establish whether the expression and activity of p42/44 MAPKs are altered in colorectal tumours as compared with normal mucosa.METHODSThe expression and activity of p42/p44 MAPK were investigated in 22 colorectal carcinomas, four adenomas, and the corresponding normal colorectal mucosa by the use of western blotting, immunoprecipitation, and in vitro kinase assays.RESULTSAfter immunoprecipitation with an antibody specific for p42 MAPK, we found significant inactivation of p42 MAPK in colonic carcinomas as well as in adenomas, whereas most sample pairs showed only minor differences in p42 MAPK expression. Investigation of MAPK with an antibody capable of detecting both p42 and p44 MAPK showed a slight but significant decrease in p44 MAPK content in malignant tissues. With this antibody, only minor alterations in MAPK activity and no correlation with p42 MAPK activity were found.CONCLUSIONSInactivation of p42 MAPK could be associated with colonic carcinogenesis.
High prevalence of NSAID enteropathy as shown by a simple faecal test
Authors: Tibble J A , Sigthorsson G , Foster R , Scott D , Fagerhol M K , Roseth A , Bjarnason I 
Published: June 2010

BACKGROUNDThe diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of 111In labelled white cells.AIMSTo assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy.METHODSSingle stool faecal calprotectin concentrations were compared with the four day faecal excretion of 111In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs.RESULTSThe four day faecal excretion of 111In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables.CONCLUSIONSAssay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.
Potentiation of cytokine induced iNOS expression in the human intestinal epithelial cell line, DLD-1, by cyclic AMP
Authors: Cavicchi M , Whittle B J R 
Published: June 2010

BACKGROUNDNitric oxide production by the inducible isoform of nitric oxide synthase (iNOS) is thought to play a role in the pathogenesis of inflammatory bowel disease along with other proinflammatory mediators.AIMSTo examine the effects of cAMP, an intracellular mediator of several proinflammatory mediators, on iNOS expression in the human intestinal epithelial cell line, DLD-1.METHODSiNOS activity was assessed by measuring the NO stable oxidative product NO2−. iNOS protein expression and iNOS mRNA levels were determined by western blotting and northern blotting, respectively.RESULTSiNOS activity, protein, and mRNA were induced by a combination of interleukin 1β (0.5–5 ng/ml), interferon γ (20–200 u/ml), and tumour necrosis factor α (10–100 ng/ml). The cytokine induced NOS activity was potentiated by N6,2′-O-dibutyryladenosine 3′:5′-cyclic monophosphate and 8-bromoadenosine 3′:5′-cyclic monophosphate (0.1–1 mM), and the adenylate cyclase activator, forskolin (1–100 μM). This activity was inhibited by the selective iNOS inhibitor, 1400W (0.1–100 μM). These agents increased iNOS protein. The cAMP analogues potentiated iNOS at the transcriptional level as shown by effects of actinomycin D (5 μg/ml) and northern blot analyses; the nuclear factor (NF) κB inhibitor, pyrrolidine dithiocarbamate (10–200 μM), significantly reduced this potentiation. The cAMP potentiated iNOS activity was inhibited by the tyrosine kinase inhibitor, A25 (10–200 μM) and the Janus activated kinase 2 inhibitor, B42 (10–200 μM).CONCLUSIONSIncreased intracellular cAMP is a potent stimulus of iNOS expression in combination with cytokines in DLD-1 cells, acting at the transcriptional level and involving NF-κB and the JAK-STAT pathways. Thus, proinflammatory mediators that increase cAMP levels may augment iNOS expression and NO production.
Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism
Authors: Pageaux G-P , Michel J , Coste V , Perney P , Possoz P , Perrigault P-F , Navarro F , Fabre J-M , Domergue J , Blanc P , Larrey D 
Published: June 2010

BACKGROUND/AIMSAlcoholic cirrhosis remains a controversial indication for liver transplantation, mainly because of ethical considerations related to the shortage of donor livers. The aim of this study was to review experience to date, focusing on survival rates and complications, and the effect of alcohol relapse on outcome and alterations in marital and socioprofessional status.METHODSThe results for 53 patients transplanted for alcoholic cirrhosis between 1989 and 1994 were compared with those for 48 patients transplanted for non-alcoholic liver disease. The following variables were analysed: survival, rejection, infection, cancer, retransplantation, employment and marital status, alcoholic recurrence. The same variables were compared between alcohol relapsers and non-relapsers.RESULTSRecovery of employment was the only significantly different variable between alcoholic (30%) and non-alcoholic patients (60%). Two factors influenced survival in the absence of alcohol recidivism: age and abstinence before transplantation. For all other variables, there were no differences between alcoholic and non-alcoholic patients, and, within the alcoholic group, between relapsers and non-relapsers. The recidivism rate was 32%.CONCLUSIONThe data indicate that liver transplantation is justified for alcoholic cirrhosis, even in cases of recidivism, which did no affect survival and compliance with the immunosuppressive regimen. These good results should help in educating the general population about alcoholic disease.
Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens
Authors: Papatheodoridis G V , Barton S G R G , Andrew D , Clewley G , Davies S , Dhillon A P , Dusheiko G , Davidson B , Rolles K , Burroughs A K 
Published: June 2010

BACKGROUNDThe role of the type of immunosuppression in the natural history of post-transplant hepatitis C virus (HCV) infection is unclear.AIMSTo evaluate the fluctuation of HCV viraemia and the early course of infection, and their relation to the type of immunosuppression in HCV transplant patients.METHODSIn 47 HCV transplant patients, serum HCV RNA levels were determined pretransplant and at one and two weeks, and three and 12 months after transplant. Initial immunosuppression was triple (cyclosporin, azathioprine, prednisolone) in 31, double (cyclosporin, prednisolone) in five, and single (cyclosporin or tacrolimus) in 11 patients. Prednisolone was withdrawn at a median of six months.RESULTSAt three months, HCV RNA levels were higher in patients with single than with triple or double initial therapy. At 12 months, HCV RNA levels correlated only with duration of prednisolone treatment and were relatively higher in patients with triple compared with single initial immunosuppression. A higher necroinflammatory activity at 12 months post-transplant was found in patients with post-transplant acute hepatitis compared with those without. Extent of fibrosis at 12 months was associated with the 12 month HCV RNA level and occurrence of post-transplant acute hepatitis.CONCLUSIONSHCV RNA levels at three months after transplant are higher in patients treated with single initial immunosuppressive therapy, but at 12 months are higher in patients with longer duration of steroid treatment. HCV viraemia at 12 months seems to be particularly important, as its levels are strongly correlated with the severity of fibrosis.
Superior mesenteric vein stenosis complicating Crohn’s disease
Authors: Hodgson R S , Jackson J E , Taylor-Robinson S D , Walters J R F 
Published: June 2010

BACKGROUNDSuperior mesenteric vein stenosis as a consequence of mesenteric fibrosis, causing the development of small bowel varices, is an unrecognised association of Crohn’s disease.CASE REPORTSTwo cases of gastrointestinal bleeding occurring in patients with Crohn’s disease, and a third case, presenting with pain and diarrhoea, are described. In all three patients, visceral angiography showed superior mesenteric vein stenosis with dilatation of draining collateral veins in the small bowel. Overt gastrointestinal bleeding or iron deficiency anaemia resulting from mucosal ulceration is common in Crohn’s disease, but acute or chronic bleeding from small bowel varices as a result of superior mesenteric vein stenosis due to fibrosis has not previously been reported.
KRASmutation and microsatellite instability in endometrial adenocarcinomas showing MELF-type myometrial invasion
Authors: Stewart C J R , Amanuel B , Grieu F , Carrello A , Iacopetta B 
Published: June 2010

BackgroundSome uterine endometrioid adenocarcinomas exhibit a distinctive morphological phenotype characterised by the formation of microcystic, elongated and fragmented (MELF) glands. Immunohistochemical studies have suggested that MELF-type changes represent an epithelial–mesenchymal transition which has been associated withKRASactivation in various tumours.AimsTo investigate the molecular characteristics of endometrial tumours showing MELF, with particular reference to the frequencies ofKRASandBRAFmutations and of microsatellite instability (MSI).MethodsMSI, andKRASandBRAFmutation status, were assessed in 33 low-grade endometrial adenocarcinomas showing MELF features and the results compared with 33 control cases exhibiting a ‘conventional’ pattern of myometrial invasion. Standard histological parameters were also reviewed.ResultsTumours with a MELF pattern of myometrial invasion showed more frequent vascular invasion and focal mucinous differentiation.KRASmutations were more frequent in MELF positive than MELF negative tumours (45% vs 30%), but this difference was not statistically significant.BRAFmutations were not identified in any of the cases. MSI was identified in 20% of cases overall but did not correlate with the MELF phenotype.ConclusionsMutations inKRASandBRAFgenes are not directly implicated in the development of a MELF pattern of invasion in endometrial carcinoma. However, RAS-associated signalling pathways could be activated through other genetic or epigenetic mechanisms. The characterisation of such alterations may become increasingly important as novel therapies are developed that target mediators involved in tumour invasion.
FISH assay development for the detection ofp16/CDKN2Adeletion in malignant pleural mesothelioma
Authors: Chung Catherine T-S , Santos Gilda Da Cunha , Hwang David M , Ludkovski Olga , Pintilie Melania , Squire Jeremy A , Tsao Ming-Sound 
Published: June 2010

AimsTo develop a fluorescence in-situ hybridisation (FISH) assay for detectingp16/CDKN2Adeletion on paraffin tissue sections for use as an ancillary test to distinguish reactive from malignant mesothelial proliferations.MethodDual-colour FISH forp16/CDKN2Aand chromosome 9 (CEP-9) was performed on 11 benign mesothelial proliferations and 54 malignant pleural mesothelioma (MPM) cases to establish cut-off values forp16/CDKN2Adeletion. A third MYC probe was used to verify cases showing homozygous deletion. Eight equivocal biopsies were used for assay testing.ResultsCut-off values forp16/CDKN2Adeletion were calculated based on FISH signalling patterns obtained from the benign controls (mean percent nuclei plus three standard deviations). Hemizygous deletion was defined as >44% of nuclei showing the hemizygous (onep16/CDKN2A, two CEP-9 signals) or >15% of nuclei showing the monosomy (onep16/CDKN2A, one CEP-9 signal) deletion patterns. None of the benign cases showed a homozygous deletion pattern (nop16/CDKN2A, at least one CEP-9 signal). In the malignant cases, the percentage of nuclei showing homozygous deletion ranged from 1% to 87%. Therefore, the cut-off value for homozygous deletion was defined as >10%.P16/CDKN2Adeletion was detected in 61% (33/54) of MPM cases. Among the equivocal biopsies, four showed homozygous and one showed hemizygousp16/CDKN2Adeletion. Age over 60 years, asbestos exposure andp16/CDKN2Adeletion were associated with a worse prognosis.ConclusionDistinction between benign and malignant mesothelial proliferations can be diagnostically challenging. FISH forp16/CDKN2Adeletion is a useful test for confirming the diagnosis of MPM.
Positive screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005–07
Authors: Streetly Allison , Latinovic Radoslav , Henthorn Joan 
Published: June 2010

AimsThe overall aim of the new national newborn programme is to identify infants at risk of sickle cell disease to allow early detection and to minimise deaths and complications.MethodsUniversal screening for sickle cell disease was introduced in England between September 2003 and July 2006. The 13 newborn laboratories each screen between 25 000 and 110 000 babies a year using the existing dried bloodspot cards. The specified conditions to be screened for include sickle cell anaemia (Hb SS), Hb SC disease, Hb S/βthalassaemia, Hb S/DPunjaband Hb S/OArab. Data are reported on screening results by ethnic group and geographical area.ResultsThe prevalence of screen positive results across England is 1:2000. There is a 25-fold variation by geographical area. African babies make up 61% of all screen positive results despite representing only 4% of total births. Combined carrier rates vary widely by ethnicity, from 1.85 per 1000 (1:540) in ‘White British’ to 145 per 1000 (1:7) in ‘African’ babies. Refusal rates for screening show variation by ethnicity.ConclusionsThese results provide useful information both about the frequency of these conditions and the carrier state and their geographic and ethnic distribution across England. This can be used to refine counselling information and are also useful to target and plan services and public information.
Runx Regulation of Sphingolipid Metabolism and Survival Signaling
Authors: Kilbey Anna , Terry Anne , Jenkins Alma , Borland Gillian , Zhang Qifeng , Wakelam Michael J.O. , Cameron Ewan R. , Neil James C. 
Published: June 2010

Abstract
The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The oncogenic potential of ectopic Runx expression has been shown in transgenic mice that develop lymphoma in potent synergy with overexpressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of overexpressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype, we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) as direct targets for Runx transcriptional regulation in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate. Runx expression also opposed the activation of c-Jun-NH2-kinase and p38MAPK, key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous tumor necrosis factor α. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate and was accompanied by reduced phosphorylation of p38MAPK. These results reveal a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance. Cancer Res; 70(14); 5860–9. ©2010 AACR.
Interleukin-27 Acts as Multifunctional Antitumor Agent in Multiple Myeloma
Authors: Cocco Claudia , Giuliani Nicola , Di Carlo Emma , Ognio Emanuela , Storti Paola , Abeltino Manuela , Sorrentino Carlo , Ponzoni Maurilio , Ribatti Domenico , Airoldi Irma 
Published: June 2010

Abstract
Purpose: Multiple myeloma (MM) derives from plasmablast/plasma cells that accumulate in the bone marrow. Different microenvironmental factors may promote metastatic dissemination especially to the skeleton, causing bone destruction. The balance between osteoclast and osteoblast activity represents a critical issue in bone remodeling. Thus, we investigated whether interluekin-27 (IL-27) may function as an antitumor agent by acting directly on MM cells and/or on osteoclasts/osteoblasts.
Experimental Design: The IL-27 direct antitumor activity on MM cells was investigated in terms of angiogenesis, proliferation, apoptosis, and chemotaxis. The IL-27 activity on osteoclast/osteoblast differentiation and function was also tested. In vivo studies were done using severe combined immunodeficient/nonobese diabetic mice injected with MM cell lines. Tumors from IL-27– and PBS-treated mice were analyzed by immunohistochemistry and PCR array.
Results: We showed that IL-27 (a) strongly inhibited tumor growth of primary MM cells and MM cell lines through inhibition of angiogenesis, (b) inhibited osteoclast differentiation and activity and induced osteoblast proliferation, and (c) damped in vivo tumorigenicity of human MM cell lines through inhibition of angiogenesis.
Conclusions: These findings show that IL-27 may represent a novel therapeutic agent capable of inhibiting directly MM cell growth as well as osteoclast differentiation and activity. Clin Cancer Res; 16(16); 4188–97. ©2010 AACR.
Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Authors: Garon Edward B. , Finn Richard S. , Hosmer Wylie , Dering Judy , Ginther Charles , Adhami Shahriar , Kamranpour Naeimeh , Pitts Sharon , Desai Amrita , Elashoff David , French Tim , Smith Paul , Slamon Dennis J. 
Published: June 2010

Abstract
Selumetinib (AZD6244; ARRY-142886) is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development. We evaluated the effects of selumetinib in 31 human breast cancer cell lines and 43 human non–small cell lung cancer (NSCLC) cell lines to identify characteristics correlating with in vitro sensitivity to MEK inhibition. IC50 &lt;1 μmol/L (considered sensitive) was seen in 5 of 31 breast cancer cell lines and 15 of 43 NSCLC cell lines, with a correlation between sensitivity and raf mutations in breast cancer cell lines (P = 0.022) and ras mutations in NSCLC cell lines (P = 0.045). Evaluation of 27 of the NSCLC cell lines with Western blots showed no clear association between MEK and phosphoinositide 3-kinase pathway activation and sensitivity to MEK inhibition. Baseline gene expression profiles were generated for each cell line using Agilent gene expression arrays to identify additional predictive markers. Genes associated with differential sensitivity to selumetinib were seen in both histologies, including a small number of genes in which differential expression was common to both histologies. In total, these results suggest that clinical trials of selumetinib in breast cancer and NSCLC might select patients whose tumors harbor raf and ras mutations, respectively. Mol Cancer Ther; 9(7); 1985–94. ©2010 AACR.
A Novel Mechanism of Indole-3-Carbinol Effects on Breast Carcinogenesis Involves Induction of Cdc25A Degradation
Authors: Wu Yongsheng , Feng Xiaoling , Jin Yucui , Wu Zhaojia , Hankey William , Paisie Carolyn , Li Lei , Liu Fengjuan , Barsky Sanford H. , Zhang Weiwei , Ganju Ramesh , Zou Xianghong 
Published: June 2010

Abstract
The natural compound indole-3-carbinol (I3C; found in vegetables of the genus Brassica) is a promising cancer prevention or therapy agent. The cell division cycle 25A (Cdc25A) phosphatase is overexpressed in a variety of human cancers and other diseases. In the present study, I3C induced degradation of Cdc25A, arrest of the G1 cell cycle, and inhibition of the growth of breast cancer cells. We also showed that the Ser124 site of Cdc25A, which is related to cyclin-dependent kinase 2, is required for I3C-induced degradation of Cdc25A in breast cancer cells, and that interruption of the ATM-Chk2 pathway suppressed I3C-induced destruction of Cdc25A. Our in vivo studies of different mutated forms of Cdc25A found that the mutation Cdc25AS124A (Ser124 to Ala124), which confers resistance to I3C-induced degradation of Cdc25A, attenuated I3C inhibition of breast tumorigenesis in a mouse xenograft model. The present in vitro and in vivo studies together show that I3C-induced activation of the ATM-Chk2 pathway and degradation of Cdc25A represent a novel molecular mechanism of I3C in arresting the G1 cell cycle and inhibiting the growth of breast cancer cells. The finding that I3C induces Cdc25A degradation underscores the potential use of this agent for preventing and treating cancers and other human diseases with Cdc25A overexpression. Cancer Prev Res; 3(7); 818–28. ©2010 AACR.