Sequencing the genome of the Atlantic salmon (<Emphasis Type="Italic">Salmo salar</Emphasis>)

The International Collaboration to Sequence the Atlantic Salmon Genome (ICSASG) will produce a genome sequence that identifies and physically maps all genes in the Atlantic salmon genome and acts as a reference sequence for other salmonids.     

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors

Background

Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.

Results

In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.

Conclusions

We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.     

The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment

Introduction  

Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections.     

Glucocorticoid receptor-JNK interaction mediates inhibition of the JNK pathway by glucocorticoids

Inhibition of the c-Jun N-terminal kinase (JNK) pathway by glucocorticoids (GCs) results in AP-1 repression. GC antagonism of AP-1 relies mainly on the transrepression function of the GC receptor (GR) and mediates essential physiological and pharmacological actions. Here we show that GCs induce the disassembly of JNK from mitogen-activated protein kinase kinase 7 (MKK7) by promoting its association with GR. Moreover, we have characterized a hormone-regulated JNK docking site in the GR ligand-binding domain that mediates GR-JNK interaction. The binding of GR to JNK is required for inhibition of JNK activation and induction of inactive JNK nuclear transfer by GCs. The dissociation of these two hormone actions shows that JNK nuclear transfer is dispensable for the downregulation of JNK activation by GCs. Nonetheless, nuclear accumulation of inactive JNK may still be relevant for enhancing the repression of AP-1 activity by GCs. In this regard, chromatin immunoprecipitation assays show that GC-induced GR-JNK association correlates with an increase in the loading of inactive JNK on the AP-1-bound response elements of the c-jun gene.     

Defective Rac-mediated proliferation and survival after targeted mutation of the beta1 integrin cytodomain

Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta1 integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the beta1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control.     

Cross-adaptation and molecular modeling study of receptor mechanisms common to four taste stimuli in humans

Psychophysical cross-adaptation experiments were performed with two carbohydrates, sucrose (SUC) and fructose (FRU), and two sweeteners, acesulfame-K (MOD) and dulcin (DUL). Seven subjects were asked to match concentrations that elicited the same intensity as a sucrose reference (30 g/l). Cross-adaptation levels were calculated as the ratio of isointense concentrations measured for a given stimulus before and under adaptation. On average, cross-adaptation between SUC and FRU is low and apparently reciprocal. By contrast, cross-adaptation between SUC and MOD is clearly non-reciprocal: SUC adapts MOD significantly (24%, P < 0.005), but MOD fails to adapt SUC (2%, P < 0.79). Significant and reciprocal cross-enhancement is observed between DUL and MOD (approximately -20%, P < 0.03), and also between SUC and DUL (approximately -15%, P < 0.08). In parallel, molecular modeling of the four tastants was performed in order to look for the 12 common binding motifs that were isolated on 14 other tastants in a previous study. SUC and FRU each display 10 out of the 12 binding motifs, whereas DUL and MOD only display four and five distinct motifs respectively and do not have any motif in common. Experimental cross-adaptation levels seem to correlate well with the number of motifs that molecules have in common. FRU and SUC share a majority of binding motifs and correlatively show mutual cross-adaptation. Four motifs of MOD are found among the 10 motifs of SUC, which may explain why SUC cross-adapts MOD but not vice versa. By contrast, DUL and MOD do not share any motif and do not cross- adapt. The various molecular mechanisms that may be responsible for cross-adaptation and/or cross-enhancement are discussed in light of our results.