Citations

Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 ( MMP1 , ANLN , CEP55 , and TFPI2 ) are known to play a role in ATC progression; however, 6/10 genes ( TMEM158 , CXCL5 , E2F7 , DLGAP5 , MME , and ASPM ) had not been specifically implicated in ATC. Similarly, 3/10 ( SFTA3 , LMO3 , and C2orf40 ) of the most globally downregulated genes were novel in this context, while 7/10 genes ( SLC26A7 , TG , TSHR , DUOX2 , CDH1 , PDE8B , and FOXE1 ) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors ( KLF16 , SP3 , ETV6 , FOXC1 , SP1 , EGFR1 , and MAFK ) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that “mitotic cell cycle” is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p -value <10 −30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

SummaryBackgroundRefractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome.AimTo create a prognostic model to estimate survival of patients with refractory coeliac disease.MethodsWe evaluated predictors of 5‐year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5‐year mortality.ResultsThe multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11–63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5‐year follow‐up (cumulative 5‐year all‐cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5‐year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38–3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22–6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61–0.85). A simple weighted three‐factor risk score was created to estimate 5‐year survival.ConclusionsUsing data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5‐year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow‐up.

Background Celiac disease (CD) occurs in approximately 1% of the Western population. It is a lifelong disorder that is associated with impaired quality of life (QOL) and an excessive risk of comorbidity and death. Objectives To review the literature on screening for CD in relation to the current World Health Organization (WHO) criteria for mass screening. Methods We performed a PubMed search to identify indexed papers on CD screening with a publication date from 1900 until 1 June 2014. When we deemed an abstract relevant, we read the corresponding paper in detail. Results CD fulfills several WHO criteria for mass screening (high prevalence, available treatment and difficult clinical detection), but it has not yet been established that treatment of asymptomatic CD may reduce the excessive risk of severe complications, leading to higher QOL nor that it is cost‐effective. Conclusions Current evidence is not sufficient to support mass screening for CD, but active case‐finding may be appropriate, as we recognize that most patients with CD will still be missed by this strategy. Although proof of benefit is still lacking, screening for CD may be appropriate in high‐risk groups.

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Key Points Zebrafish flt3 plays an important role in the initiation of definitive hematopoietic stem cells. Expression of human FLT3-ITD activates endogenous flt3 signaling and induces myeloid expansion.

Quantifying the pathological features of flexor tendon pulleys is essential for grading the trigger finger since it provides clinicians with objective evidence derived from microscopic images. Although manual grading is time consuming and dependent on the observer experience, there is a lack of image processing methods for automatically extracting pulley pathological features. In this paper, we design and develop a color-based image segmentation system to extract the color and shape features from pulley microscopic images. Two parameters which are the size ratio of abnormal tissue regions and the number ratio of abnormal nuclei are estimated as the pathological progression indices. The automatic quantification results show clear discrimination among different levels of diseased pulley specimens which are prone to misjudgments for human visual inspection. The proposed system provides a reliable and automatic way to obtain pathological parameters instead of manual evaluation which is with intra- and interoperator variability. Experiments with 290 microscopic images from 29 pulley specimens show good correspondence with pathologist expectations. Hence, the proposed system has great potential for assisting clinical experts in routine histopathological examinations.

Abstract Introduction Cytidine drugs, such as gemcitabine, undergo rapid, inactivating catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine drug metabolism. However, p.o. THU is at most 20% bioavailable (Beumer et al.), which limits its preclinical evaluation and clinical use. Therefore, the more lipophilic prodrug triacetyl THU (taTHU) was developed. We characterized THU pharmacokinetics after administration of taTHU to mice. Methods Mice were dosed 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters and p.o. bioavailability were calculated non-compartmentally and compartmentally. We assessed taTHU inhibition of metabolism of gemcitabine by recombinant CD. ResultsTHU parameterstaTHU i.v. 150 mg/kgtaTHU p.o. 150 mg/kgCmax (µg/mL)10611.8Tmax (min)560Half-life (min)235122AUC0-inf (mg/mL*min)7.553.36Vd/F (L/kg)4.495.26Cl/F (mL/min/kg)13.229.8F-THUi.v. (%)68.030.3% dose in 0-16 h urine405.6% dose in 0-24 h urine5512 THU, after 150 mg/kg taTHU i.v., had a 235 min terminal half-life and produced plasma THU concentrations &gt;1 µg/mL, the concentration shown to inhibit CD, for 10 h. A multi-compartment model fit the data best. 150 mg/kg p.o. taTHU produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5-2 h, followed by a decline with a 122 min half-life. Approximately 68% of i.v. taTHU was converted to THU. Approximately 30% of p.o. taTHU reached the systemic circulation as THU. After i.v dosing, renal excretion accounted for 40-55% of the taTHU dose, 26-35% as THU and an additional 14-19% as acetylated forms of THU. After p.o. dosing, the renal excretion percentages were 6-12%, 5.2-11%, and 0.42-0.71%, respectively. taTHU did not inhibit recombinant CD. Conclusion The availability of THU after p.o. taTHU in mice is 30%, as compared to the 20% achieved after p.o. THU. Clinical studies are warranted to evaluate availability of THU from taTHU in humans. Support: N01-CM07106, N01-CM52202, P30-CA47904 from the NCI and P41-EB001978. 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 4549.

Recent evidence suggests that alveolar epithelial cells (AECs) may contribute to the development, propagation, and resolution of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proinflammatory cytokines, pathogen products, and injurious mechanical ventilation are important contributors of excessive inflammatory responses in the lung. In the present study, we used cDNA microarrays to define the gene expression patterns of A549 cells (an AEC line) in the early stages of three models of pulmonary parenchymal cell activation: cells treated with tumor necrosis factor-α (TNFα) (20 ng/ml), lipopolysaccharide (LPS, 1 μg/ml), or cyclic stretch (20% elongation) for either 1 h or 4 h. Differential gene expression profiles were determined by gene array analysis. TNFα induced an inflammatory response pattern, including induction of genes for chemokines, inflammatory mediators, and cell surface membrane proteins. TNFα also increased genes related to pro- and anti-apoptotic proteins, signal transduction proteins, and transcriptional factors. TNFα further induced a group of genes that may form a negative feedback loop to silence the NFκB pathway. Stimulation of AECs with mechanical stretch changed cell morphology and activated Src protein tyrosine kinase. The combination of TNFα plus stretch enhanced or attenuated expression of multiple genes. LPS decreased microfilament polymerization but had less impact on NFκB translocation and gene expression. Results from this study indicate that AECs can tailor their response to different stimuli or/and combination of stimuli and subsequently play an important role in acute inflammatory responses in the lung.