Smoothing Out Drug Resistance

Smoothened inhibitors have emerged as successful treatment alternatives for Hedgehog pathway-dependent tumors, but they are linked with the appearance of drug resistance. In this issue of Cancer Cell, Kim and colleagues overcome such resistance by combining approved drugs itraconazole and arsenic trioxide, thus opening a path toward new treatment options

Symptoms in smokers trying to quit

AIMS: To describe the prevalence and intensity of different symptoms in relation to tobacco abstinence. To explore latent dimensions between symptoms in smokers trying to quit. DESIGN: A cross sectional study using a questionnaire to retrospectively assess symptoms over a period of 12 months. SETTING: Swedish telephone quitline, a nationwide free of charge service. PARTICIPANTS: All 741 individuals who had called the quitline and signed up for smoking cessation treatment between February 2000 to November 2001 and reported to have been smoke free for at least 24 hours during the previous 12 month period from first contact. MEASUREMENTS: Assessments were made by self-report, and abstinence was defined as "not a single puff of smoke during the last week". A factor analysis approach where individual items aggregate into factors was used to explore the relationship between the different symptoms. FINDINGS: High intensity of symptoms related to unsuccessful quitting attempts and included craving, irritability, apprehension/anxiety, difficulties concentrating, restlessness, depression/depressed mood, and insomnia. The factor loadings of all 17 symptoms resulted in three factors with factor 1, psychological being the most important. High scores on this factor relates to unsuccessful quitting attempts. Using Nicotine Replacement Therapy (NRT) for 5 weeks or longer, reduced symptoms included in factor 1. The other two factors were factor 2 physiological and factor 3 neurological. CONCLUSION: Symptoms that are psychological and/or neurological in nature are interrelated and appear to be the most significant obstacles for successful quitting attempts in a population-based setting. These symptoms may be successfully treated with NRT.NonePublishe

ETNISK LIGETILLING PÅ ARBEJDSMARKEDET GENNEM ÆNDRING AF DISKURSIV PRAKSIS OM KULTUR

Artiklen bygger på vores speciale »Kulturel Kompleksitet på Arbejdsmarkedet i Danmark«, der omfatter en undersøgelse af integration på arbejdsmarkedet. Artiklen har en diskussion af kulturel identitet og interkulturel kommunikation i det globaliserede samfund som sit omdrejningspunkt – set fra et postmoderne perspektiv. Med udgangspunkt i kvalitative interviews diskuterer vi, hvad diskurser om kultur kan betyde for relationen mellem nogle firmapartnere med forskellige tilknytninger til det danske nationale fællesskab, og hvordan deres oplevelser af integration kan inspirere til nye tiltag for at fremme etnisk ligestilling på landets arbejdspladser. Vi konkluderer bl.a., at en ændring af diskursiv praksis i forhold til kultur, fra en klassisk til en kontekstorienteret kulturforståelse, er en forudsætning for at skabe etnisk ligestilling på arbejdsmarkedet i Danmar

The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor

Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene. In most cases the second wild-type allele is lost in tumor tissue, suggesting that CYLD functions as tumor suppressor. CYLD is a protein of 956 amino acids harboring a functional deubiquitinating domain at the COOH-terminal end. To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD. Mapping of the interacting domains revealed that the central domain of CYLD binds to the COOH-terminal end of TRIP. Far Western analysis and coimmunoprecipitations in mammalian cells confirmed that full-length CYLD binds to the COOH-terminal domain of TRIP. Because TRIP is an inhibitor of nuclear factor (NF)-κB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-κB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-κB activation by TNF-α. The inhibition by CYLD depends on the presence of the central domain interacting with TRIP and its deubiquitinating activity. These findings indicate that cylindromas arise through constitutive NF-κB activation leading to hyperproliferation and tumor growth

Gorlin syndrome associated with small bowel carcinoma and mesenchymal proliferation of the gastrointestinal tract: case report and review of literature

<p>Abstract</p> <p>Background and Case Presentation</p> <p>A patient with nevoid basal cell carcinoma syndrome (Gorlin syndrome) presented with two unusual clinical features, i.e. adenocarcinoma of the small bowel and extensive mesenchymal proliferation of the lower gastrointestinal tract.</p> <p>Conclusions</p> <p>We discuss the possibility that these two features are pathogenetically linked to the formerly undescribed patient's <it>PTCH </it>germ line mutation.</p

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma

The FU gene and its possible protein isoforms

BACKGROUND: FU is the human homologue of the Drosophila gene fused whose product fused is a positive regulator of the transcription factor Cubitus interruptus (Ci). Thus, FU may act as a regulator of the human counterparts of Ci, the GLI transcription factors. Since Ci and GLI are targets of Hedgehog signaling in development and morphogenesis, it is expected that FU plays an important role in Sonic, Desert and/or Indian Hedgehog induced cellular signaling. RESULTS: The FU gene was identified on chromosome 2q35 at 217.56 Mb and its exon-intron organization determined. The human developmental disorder Syndactyly type 1 (SD1) maps to this region on chromosome 2 and the FU coding region was sequenced using genomic DNA from an affected individual in a linked family. While no FU mutations were found, three single nucleotide polymorphisms were identified. The expression pattern of FU was thoroughly investigated and all examined tissues express FU. It is also clear that different tissues express transcripts of different sizes and some tissues express more than one transcript. By means of nested PCR of specific regions in RT/PCR generated cDNA, it was possible to verify two alternative splicing events. This also suggests the existence of at least two additional protein isoforms besides the FU protein that has previously been described. This long FU and a much shorter isoform were compared for the ability to regulate GLI1 and GLI2. None of the FU isoforms showed any effects on GLI1 induced transcription but the long form can enhance GLI2 activity. Apparently FU did not have any effect on SUFU induced inhibition of GLI. CONCLUSIONS: The FU gene and its genomic structure was identified. FU is a candidate gene for SD1, but we have not identified a pathogenic mutation in the FU coding region in a family with SD1. The sequence information and expression analyses show that transcripts of different sizes are expressed and subjected to alternative splicing. Thus, mRNAs may contain different 5'UTRs and encode different protein isoforms. Furthermore, FU is able to enhance the activity of GLI2 but not of GLI1, implicating FU in some aspects of Hedgehog signaling

Increased Expression of the Dyslexia Candidate Gene DCDC2 Affects Length and Signaling of Primary Cilia in Neurons

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