MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

The Interplay Between GUT and Flavour Symmetries in a Pati-Salam x S4 Model

Both Grand Unified symmetries and discrete flavour symmetries are appealing ways to describe apparent structures in the gauge and flavour sectors of the Standard Model. Both symmetries put constraints on the high energy behaviour of the theory. This can give rise to unexpected interplay when building models that possess both symmetries. We investigate on the possibility to combine a Pati-Salam model with the discrete flavour symmetry $S_4$ that gives rise to quark-lepton complementarity. Under appropriate assumptions at the GUT scale, the model reproduces fermion masses and mixings both in the quark and in the lepton sectors. We show that in particular the Higgs sector and the running Yukawa couplings are strongly affected by the combined constraints of the Grand Unified and family symmetries. This in turn reduces the phenomenologically viable parameter space, with high energy mass scales confined to a small region and some parameters in the neutrino sector slightly unnatural. In the allowed regions, we can reproduce the quark masses and the CKM matrix. In the lepton sector, we reproduce the charged lepton masses, including bottom-tau unification and the Georgi-Jarlskog relation as well as the two known angles of the PMNS matrix. The neutrino mass spectrum can present a normal or an inverse hierarchy, and only allowing the neutrino parameters to spread into a range of values between $\lambda^{-2}$ and $\lambda^2$, with $\lambda\simeq0.2$. Finally, our model suggests that the reactor mixing angle is close to its current experimental bound.Comment: 62 pages, 4 figures; references added, version accepted for publication in JHE

Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in adults and children aged 12 years and over

Meta-AnalysisResearch Support, Non-U.S. Gov'tReviewThis is a freely-available open access publication. Please cite the published version which is available via the DOI link in this recordOBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in adults and children aged over 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies was conducted. Cost comparison and cost-consequence analyses were performed where appropriate. RESULTS: The assessment of clinical effectiveness was based on the 67 randomised controlled trials selected from the 5175 reports identified through the systematic literature search. The most frequently reported relevant outcomes were lung function, symptoms, use of rescue medication and adverse events. The trials varied considerably. In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, there were few significant differences in clinical effectiveness, although a few of the trials had assessed non-inferiority between the comparators rather than superiority. At doses of 400, 800 and 'high-level' doses of 1500 or 1600 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. A significant treatment benefit for combination ICS/LABA therapy across a range of outcomes compared with ICS alone was identified [when the ICS was double the accepted clinically equivalent dose of the ICS in the combination inhaler, and dry powder inhalers (DPIS) were used to deliver the drugs]. When a formoterol fumarate (FF)/salmeterol (SAL) combination inhaler and a budesonide (BUD)/FF combination inhaler were each compared with their constituent drugs delivered in separate inhalers, there were very few statistically significant differences between the treatments across the various efficacy outcomes and the rate of adverse events. Combination inhalers were more often cheaper than doubling the dose of ICS alone. However, the costs were highly variable and dependent on both the dose required and the preparation used in the trials. The estimated mean annual cost of FP/SAL combination varied from being 94 pounds cheaper to 109 pounds more expensive than the alternative of BUD at a higher dose. The BUD/FF combination varied from being 163 pounds cheaper to 66 pounds more expensive than the higher dose of either BUD or FP. When the combination inhalers were compared to each other, the results were mixed, with the FP/SAL combination significantly superior on some outcomes and the BUD/FF combination superior on others; however, meta-analysis showed that there were no significant differences between the two treatments in the rate of adverse events. Taking an ICS with a LABA as either of the two currently available combination products, FP/SAL and BUD/FF, is usually cheaper than taking the relevant constituent drugs in separate inhalers. At very high doses of BUD (1600 microg/day), however, the BUD/FF combination inhaler can be up to 156 pounds more expensive than having the same drugs in separate inhalers. In terms of the relative costs associated with taking one of the combination inhalers, at low dose (400 microg BUD or 200 microg FP/day) the cheapest combination inhaler is FP/SAL as a pressurised metered dose inhaler (pMDI) (Seretide Evohaler). However, this is only slightly cheaper than using BUD/FF as a DPI (Symbicort Turbohaler). At higher dose levels (800 microg BUD or 500 microg FP/day) FP/SAL as either pMDI aerosol (Seretide Evohaler) or a DPI (Seretide Accuhaler) is the cheapest combination product available, but again only slightly cheaper than the DPI BUD/FF combination (Symbicort Turbohaler). It should be highlighted, however, that the three head-to-head trials that compared the effects of FP/SAL with BUD/FF used the FP/SAL DPI combination inhaler, Seretide Accuhaler. CONCLUSIONS: The evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available and tend to remain so as the daily ICS dose required increases. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed for all outcome measures. The cost differences between combination therapy compared with ICS monotherapy are highly variable and dependent on the dose required and the particular preparations used. For the combination therapies of ICS/LABA there are potential cost savings with the use of combination inhalers compared with separate inhalers, with few differences between the two treatment strategies in terms of effects. The only exception to this cost saving is with BUD/FF at doses higher than 1200 microg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. Neither of the two combination inhalers (FP/SAL or BUD/FF) is consistently superior in terms of treatment effect. A comparison of the costs associated with each combination therapy indicates that at low dose FP/SAL delivered via a pMDI is currently the cheapest combination inhaler but only marginally cheaper than BUD/FF delivered as a DPI. At higher doses, both the FP/SAL combination inhalers (PMDI and DPI) are marginally cheaper than BUD/FF (DPI). Future trials of treatment for chronic asthma should standardise the way in which outcome measures are defined and measured, with a greater focus on patient-centred outcomes. For informing future cost-utility and cost-effectiveness analyses from a UK NHS perspective, there is a need for longitudinal studies that comprehensively track the care pathways followed when people experience asthma exacerbations of different severity. Further research synthesis, quantifying the adverse effects of the different ICS, is required for treatment choices by patients and clinicians to be fully informed.HTA Programme, NIC

The use of the multivariate Principal Response Curve (PRC) for community analysis: a case study on the effects of carbendazim on enchytraeids in Terrestrial Model Ecosystems (TME).

The effects of the fungicide carbendazim (formulation Derosal®) on enchytraeids were determined in Terrestrial Model Ecosystem (TME) tests. TMEs consisted of intact soil columns (diameter 17.5 cm; length 40 cm) taken from three grassland sites (Amsterdam (The Netherlands), Bangor (Wales, England) and Flörsheim (Germany)) or an arable site (Coimbra (Portugal)). Results for each TME site were evaluated using the multivariate Principal Response Curve (PRC) method. The resulting No-Observable Effect Concentrations (NOECs) for the community were compared with the NOECs generated by univariate statistical methods. Furthermore, the E

TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.

Abstract TGF-ß/Activin induces epithelial-to-mesenchymal transition (EMT) and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-ß transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-ß also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-ß-mediated response indicating that these miRNAs are important TGF-ß effectors. We integrated AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions’ pathways. Together, we uncover that TGF-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis

Demographic parameters of reintroduced grey partridges in central Italy and the effect of weather

International audienceGrey partridge populations declined in Europe from mid-1950s onwards mostly due to modifications of agricultural cropping. In Italy, the decline was even more dramatic because of over-hunting and restocking with allochthonous birds. We carried out a research on a re-introduced population in Central Italy from 1995 to 2005, with the aim of evaluating the reintroduction success and separating the intrinsic and external factors influencing year-to-year changes in partridge density with particular respect to the weather. Average spring density was 4.5 pairs per square kilometre (SD = 1.52); our population reached a peak few years after the reintroduction and then declined. Brood production rate was close to that of declining European populations (average 33.9%; SD = 10.21), and chick survival rate (average 40%; = 17.61) determined the change of breeding abundance from year to year + 1. Our population seemed to be mainly affected by brood production and chick survival rates and by the weather; in particular, higher early winter and spring temperatures increased breeding density whilst higher early summer temperatures decreased brood production rate

Do Children and Adolescents with Anorexia Nervosa Display an Inefficient Cognitive Processing Style?

Objective: This study aimed to examine neuropsychological processing in children and adolescents with Anorexia Nervosa (AN). The relationship of clinical and demographic variables to neuropsychological functioning within the AN group was also explored.  Method: The performance of 41 children and adolescents with a diagnosis of AN were compared to 43 healthy control (HC) participants on a number of neuropsychological measures.  Results: There were no differences in IQ between AN and HC groups. However, children and adolescents with AN displayed significantly more perseverative errors on the Wisconsin Card Sorting Test, and lower Style and Central Coherence scores on the Rey Osterrieth Complex Figure Test relative to HCs.  Conclusion: Inefficient cognitive processing in the AN group was independent of clinical and demographic variables, suggesting it might represent an underlying trait for AN. The implications of these findings are discussed

Chiral matter wavefunctions in warped compactifications

We analyze the wavefunctions for open strings stretching between intersecting 7-branes in type IIB/F-theory warped compactifications, as a first step in understanding the warped effective field theory of 4d chiral fermions. While in general the equations of motion do not seem to admit a simple analytic solution, we provide a method for solving the wavefunctions in the case of weak warping. The method describes warped zero modes as a perturbative expansion in the unwarped spectrum, the coefficients of the expansion depending on the warping. We perform our analysis with and without the presence of worldvolume fluxes, illustrating the procedure with some examples. Finally, we comment on the warped effective field theory for the modes at the intersection.Comment: 64 pages, 1 figure. References updated, typos fixed, discussion on varying dilaton case slightly modified. Version to appear in JHE

Lepton flavor violating \u3c4 decays in TeV scale type i see-saw and Higgs triplet models

The lepton flavour violating (LFV) \u3c4 decays \u3c4 \u2192 (e, \u3bc)\u3b3 and \u3c4 \u2192 3\u3bc are investigated in the frameworks of the TeV scale type I see-saw and Higgs Triplet (or type II see-saw) models. Predictions for the rates of these processes are obtained. The implications of the existing stringent experimental upper bounds on the \u3bc \u2192 e + \u3b3 and \u3bc \u2192 3e decay branching ratios for the predictions of the \u3c4 \u2192 (e, \u3bc)\u3b3 and \u3c4 \u2192 3\u3bc decay rates are studied in detail. The possibilities to observe the indicated LFV \u3c4 decays in present and future experiments are analysed. \ua9 2013 SISSA, Trieste, Italy