Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.

BackgroundPancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.MethodsWe characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.ResultsNT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.ConclusionsFavorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease

The Contrast Model of Similarity and Comparative Advertising

Two studies are reported which examine the existence of attribute redundancy as well as consumers\u27 ability to perceive attribute redundancy in consumer information environments. The results of the first study suggest that attribute redundancy varies widely from product category to product category. The results of the second study suggest that consumers\u27 ability to perceive attribute relationships improves with product knowledge. Unexpected was an observed U-shaped relationship between consumers\u27 perceptions of attribute redundancy and attribute knowledge. Together the results suggest a number of policy implications regarding the value of consumer information programs

An Examination of the Validity of Direct Product Perceptions

The validity of a class of direct product perceptions is examined. Consumers recorded their perception of different products directly within existing spatial or treelike representations of the products’ competitors. A conceptual model is developed that describes consumers’ ability to provide direct perceptions within both space and tree representations for both brands and product categories. An empirical study is reported which supports the model and the validity of the recorded perceptions

Effects of an abasic site on triple helix formation characterized by affinity cleaving

The stability of triple helical complexes of pyrimidine oligodeoxyribonucleotides containing one abasic 1,2- dideoxy-D-ribose (ø) residue was examined by affinity cleaving. Within a pyrimidine third strand, the triplets ø·AT, ø·GC, ø·TA and ø·CG are significantly less stable than the triplets, T- AT, C + GC and GTA. The decrease in binding produced by an abasic residue is similar to that observed with imperfectly matched natural base triplets, with ø · AT and ø · GC being less stable than ø · TA and ø · CG triplets for the sequences studied

Fermion self-trapping in the optical geometry of Einstein-Dirac solitons

Funding: St Leonards scholarship from the University of St Andrews and from UKRI under EPSRC Grant No. EP/R513337/1 (P.E.D.L).We analyze gravitationally localized states of multiple fermions with high angular momenta, in the formalism introduced by Finster, Smoller, and Yau [Phys Rev. D 59, 104020 (1999)]. We show that the resulting solitonlike wave functions can be naturally interpreted in terms of a form of self-trapping, where the fermions become localized on shells the locations of which correspond to those of “bulges” in the optical geometry created by their own energy density.Publisher PDFPeer reviewe

Nonlinear effects in the excited states of many-fermion Einstein-Dirac solitons

Funding: P. E. D. L. acknowledges funding from a St Leonards scholarship from the University of St Andrews and from UKRI under EPSRC Grant No. EP/R513337/1.We present an analysis of excited-state solutions for a gravitationally localized system consisting of a filled shell of high-angular-momentum fermions, using the Einstein-Dirac formalism introduced by Finster, Smoller, and Yau [Phys. Rev. D 59, 104020 (1999)]. We show that, even when the particle number is relatively low (Nf ≥ 6), the increased nonlinearity in the system causes a significant deviation in behavior from the two-fermion case. Excited-state solutions can no longer be uniquely identified by the value of their central redshift, with this multiplicity producing distortions in the characteristic spiraling forms of the mass-radius relations. We discuss the connection between this effect and the internal structure of solutions in the relativistic regime.Publisher PDFPeer reviewe

Effects of an abasic site on triple helix formation characterized by affinity cleaving

The stability of triple helical complexes of pyrimidine oligodeoxyribonucleotides containing one abasic 1,2- dideoxy-D-ribose (ø) residue was examined by affinity cleaving. Within a pyrimidine third strand, the triplets ø·AT, ø·GC, ø·TA and ø·CG are significantly less stable than the triplets, T- AT, C + GC and GTA. The decrease in binding produced by an abasic residue is similar to that observed with imperfectly matched natural base triplets, with ø · AT and ø · GC being less stable than ø · TA and ø · CG triplets for the sequences studied

Yogurt made from milk heated at different pH values

Milk for yogurt manufacture is subjected to high heat treatment to denature whey proteins. Low milk pH values (= 7.0) at heating result in the formation of mostly soluble (nonmicellar) denatured whey protein complexes. There are conflicting reports on the relative importance of soluble and casein-bound whey protein aggregates on the properties of acid gels. Prior studies investigating the effect of pH of milk at heating used model gels in which milk was acidified by glucono-delta-lactone; in this study, we prepared yogurt gels using commercial starter cultures. Model acid gels can have very different texture and physical properties from those made by fermentation with starter cultures. In this study, we investigated the effects of different pH values of milk at heating on the rheological, light backscatter, and microstructural properties of yogurt gels. Reconstituted skim milk was adjusted to pH values 6.2, 6.7, and 7.2 and heated at 85 degrees C for 30 min. A portion of the heated milk samples was readjusted back to pH 6.7 after heating. Milks were inoculated with 3% (wt/wt) yogurt starter culture and incubated at 40 degrees C until pH 4.6. Gel formation was monitored using dynamic oscillatory rheology, and parameters measured included the storage modulus (G') and loss tangent (LT) values. Light-backscattering properties, such as the backscatter ratio (R) and the first derivative of light backscatter ratio (R'), were also monitored during fermentation. Fluorescence microscopy was used to observe gel microstructure. The G' values at pH 4.6 were highest in gels made from milk heated at pH 6.7 and lowest in milk heated at pH 6.2, with or without pH adjustment after heating. The G' values at pH 4.6 were lower in samples after adjustment back to pH 6.7 after heating. No maximum in the LT parameter was observed during gelation for yogurts made from milk heated at pH 6.2; a maximum in LT was observed at pH similar to 4.8 for samples heated at pH 6.7 or 7.2, with or without pH adjustment after heating. Higher R-values were observed with an increase in pH of heating, with or without pH adjustment after heating. The sample heated at pH 6.2 had only one major peak in its R' profile during acidification, whereas samples heated at pH 6.7 and 7.2 had 2 large peaks. The lack of a maximum in LT parameter and the presence of a single peak in the R' profile for the samples heated at pH 6.2 were likely due to the partial solubilization of insoluble calcium phosphate when milk was acidified to this lower pH value. No clear differences were observed in the microstructures of gels between the different treatments. This study indicates that heating milk at the natural pH (similar to 6.7) created an optimum balance of casein-bound and soluble denatured whey proteins, which resulted in yogurt with the highest gel stiffness.University of Wisconsin-Madiso