Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Two spatiotemporally distinct value systems shape reward-based learning in the human brain

Avoiding repeated mistakes and learning to reinforce rewarding decisions is critical for human survival and adaptive actions. Yet, the neural underpinnings of the value systems that encode different decision-outcomes remain elusive. Here coupling single-trial electroencephalography with simultaneously acquired functional magnetic resonance imaging, we uncover the spatiotemporal dynamics of two separate but interacting value systems encoding decision-outcomes. Consistent with a role in regulating alertness and switching behaviours, an early system is activated only by negative outcomes and engages arousal-related and motor-preparatory brain structures. Consistent with a role in reward-based learning, a later system differentially suppresses or activates regions of the human reward network in response to negative and positive outcomes, respectively. Following negative outcomes, the early system interacts and downregulates the late system, through a thalamic interaction with the ventral striatum. Critically, the strength of this coupling predicts participants’ switching behaviour and avoidance learning, directly implicating the thalamostriatal pathway in reward-based learning

Questionnaire of chronic illness care in primary care-psychometric properties and test-retest reliability

<p>Abstract</p> <p>Background</p> <p>The Chronic Care Model (CCM) is an evidence-based approach to improving the structure of care for chronically ill patients with multimorbidity. The Assessment of Chronic Illness Care (ACIC), an instrument commonly used in international research, includes all aspects of the CCM, but cannot be easily extended to the German context. A new instrument called the "Questionnaire of Chronic Illness Care in Primary Care" (QCPC) was developed for use in Germany for this reason. Here, we present the results of the psychometric properties and test-retest reliability of QCPC.</p> <p>Methods</p> <p>A total of 109 family doctors from different German states participated in the validation study. Participating physicians completed the QCPC, which includes items concerning the CCM and practice structure, at baseline (T0) and 3 weeks later (T1). Internal consistency reliability and test-retest reliability were evaluated using Cronbach's alpha and Pearson's r, respectively.</p> <p>Results</p> <p>The QCPC contains five elements of the CCM (decision support, delivery system design, self-management support, clinical information systems, and community linkages). All subscales demonstrated moderate internal consistency and moderate test-retest reliability over a three-week interval.</p> <p>Conclusions</p> <p>The QCPC is an appropriate instrument to assess the structure of chronic illness care. Unlike the ACIC, the QCPC can be used by health care providers without CCM training. The QCPC can detect the actual state of care as well as areas for improvement of care according to the CCM.</p

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies

Gene Expression Profiling of Preovulatory Follicle in the Buffalo Cow: Effects of Increased IGF-I Concentration on Periovulatory Events

The preovulatory follicle in response to gonadotropin surge undergoes dramatic biochemical, and morphological changes orchestrated by expression changes in hundreds of genes. Employing well characterized bovine preovulatory follicle model, granulosa cells (GCs) and follicle wall were collected from the preovulatory follicle before, 1, 10 and 22 h post peak LH surge. Microarray analysis performed on GCs revealed that 450 and 111 genes were differentially expressed at 1 and 22 h post peak LH surge, respectively. For validation, qPCR and immunocytochemistry analyses were carried out for some of the differentially expressed genes. Expression analysis of many of these genes showed distinct expression patterns in GCs and the follicle wall. To study molecular functions and genetic networks, microarray data was analyzed using Ingenuity Pathway Analysis which revealed majority of the differentially expressed genes to cluster within processes like steroidogenesis, cell survival and cell differentiation. In the ovarian follicle, IGF-I is established to be an important regulator of the above mentioned molecular functions. Thus, further experiments were conducted to verify the effects of increased intrafollicular IGF-I levels on the expression of genes associated with the above mentioned processes. For this purpose, buffalo cows were administered with exogenous bGH to transiently increase circulating and intrafollicular concentrations of IGF-I. The results indicated that increased intrafollicular concentrations of IGF-I caused changes in expression of genes associated with steroidogenesis (StAR, SRF) and apoptosis (BCL-2, FKHR, PAWR). These results taken together suggest that onset of gonadotropin surge triggers activation of various biological pathways and that the effects of growth factors and peptides on gonadotropin actions could be examined during preovulatory follicle development

Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy

Herein we report the development and biological screening of a bioorthogonal palladium-labile prodrug of the nucleoside analogue floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast reduction of its biological activity (~6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chemistry both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy

Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss

Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing

Drug suicide: a sex-equal cause of death in 16 European countries

Background: There is a lack of international research on suicide by drug overdose as a preventable suicide method. Sex- and age-specific rates of suicide by drug self-poisoning (ICD-10, X60-64) and the distribution of drug types used in 16 European countries were studied, and compared with other self-poisoning methods (X65-69) and intentional self-injury (X70-84).Methods: Data for 2000-04/05 were collected from national statistical offices. Age-adjusted suicide rates, and age and sex distributions, were calculated.Results: No pronounced sex differences in drug self-poisoning rates were found, either in the aggregate data (males 1.6 and females 1.5 per 100,000) or within individual countries. Among the 16 countries, the range (from some 0.3 in Portugal to 5.0 in Finland) was wide. 'Other and unspecified drugs' (X64) were recorded most frequently, with a range of 0.2-1.9, and accounted for more than 70% of deaths by drug overdose in France, Luxembourg, Portugal and Spain. Psychotropic drugs (X61) ranked second. The X63 category ('other drugs acting on the autonomic nervous system') was least frequently used. Finland showed low X64 and high X61 figures, Scotland had high levels of X62 ('narcotics and hallucinogens, not elsewhere classified') for both sexes, while England exceeded other countries in category X60. Risk was highest among the middle-aged everywhere except in Switzerland, where the elderly were most at risk.Conclusions: Suicide by drug overdose is preventable. Intentional self-poisoning with drugs kills as many males as females. The considerable differences in patterns of self-poisoning found in the various European countries are relevant to national efforts to improve diagnostics of suicide and appropriate specific prevention. The fact that vast majority of drug-overdose suicides came under the category X64 refers to the need of more detailed ICD coding system for overdose suicides is needed to permit better design of suicide-prevention strategies at national level