Hedgehog Signaling in Prostate Cancer and Its Therapeutic Implication

Activation of Hedgehog (Hh) signaling is implicated in the development and progression of several tumor types, including prostate cancer, which is still the most common non-skin malignancy and the third leading cause of cancer-related mortality in men in industrialized countries worldwide. Several studies have indicated that the Hh pathway plays a crucial role in the development as well as in the progression of this disease to more aggressive and even therapy-resistant disease states. Moreover, preclinical data have shown that inhibition of Hh signaling has the potential to reduce prostate cancer invasiveness and metastatic potential. Clinical trials investigating the benefit of Hh inhibitors in patients with prostate cancer have recently been initiated. However, acquired drug resistance has already been observed in other tumor types after long-term Hh inhibition. Therefore, combining Hh inhibitors with ionizing radiation, chemotherapy or other molecular targeted agents could represent an alternative therapeutic strategy. In this review, we will highlight the role of Hh signaling in the development and progression of prostate cancer and summarize the different therapeutic applications of Hedgehog inhibition.     

Pseudo-Starvation Driven Energy Expenditure Negatively Affects Ovarian Follicle Development

In the present investigation, we examined whether a change in whole body energy fluxes could affect ovarian follicular development, employing mice ectopically expressing uncoupling protein 1 in skeletal muscle (UCP1-TG). Female UCP1-TG and wild-type (WT) mice were dissected at the age of 12 weeks. Energy intake and expenditure, activity, body weight and length, and body composition were measured. Plasma insulin, glucose, leptin, plasma fibroblast growth factor 21 (FGF21) and plasma insulin-like growth factor 1 (IGF1) levels were analyzed and ovarian follicle and corpus luteum numbers were counted. IGF1 signaling was analyzed by immunohistochemical staining for the activation of insulin receptor substrate 1/2 (IRS1/2) and AKT. UCP1-TG female mice had increased energy expenditure, reduced body size, maintained adiposity, and decreased IGF1 concentrations compared to their WT littermates, while preantral and antral follicle numbers were reduced by 40% and 60%, respectively. Corpora lutea were absent in 40% of the ovaries of UCP1-TG mice. Phospho-IRS1, phospho-AKT -Ser473 and -Thr308 immunostaining was present in the granulosa cells of antral follicles in WT ovaries, but faint to absent in the antral follicles of UCP1-TG mice. In conclusion, the reduction in circulating IGF1 levels due to the ectopic expression of UCP1 is associated with reduced immunostaining of the IRS1-PI3/AKT pathway, which may negatively affect ovarian follicle development and ovulation.     

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.     

Inorganic polymers made of fayalite slag: On the microstructure and behavior of Fe

The microstructure of inorganic polymers (IP) formed from fayalite slag was investigated as a function of the composition of different activating solutions. The starting slag was 80 wt% amorphous, and after activation using sodium silicate solutions with varying SiO₂/Na₂O molar ratios, the amorphous phase dissolved and a binder phase was formed. The morphology of this binder, including the population and size of remnant particles and pores, was dependent on the particular activating solution used, and became denser as the level of silicate rose. ⁵⁷Fe Mössbauer spectroscopy revealed that the IP synthesis reaction is combined with the oxidation of Fe²⁺ from the fayalite slag to Fe³⁺ in the inorganic polymer binder. The reaction extent varied and could be quantified using the absorption areas of these ions. Data corroborate that the Fe²⁺ ions in the amorphous part of the fayalite slag and the Fe³⁺ ions in the new binder phase had an average oxygen‐coordination number of 5.     

Influence of FeO/SiO2 and CaO/SiO2 Ratios in Iron‐Saturated ZnO‐Rich Fayalite Slags on the Corrosion of MgO

The corrosion behavior of MgO in iron‐saturated ZnO‐rich fayalite (ZFS) slags having various FeO/SiO₂ ratio and CaO/SiO₂ ratio was investigated using MgO crucible tests for 12 h at 1200°C. The FeO/SiO₂ and CaO/SiO₂ ratios in the ZFS slags were varied from 1.0 to 2.2, and from 0.04 to 0.32, respectively. In all of the tests, it was observed that MgO dissolves into ZFS slags and that (Zn,Fe,Mg)₂SiO₄ olivine and (Zn,Fe,Mg)O solid solution are formed at the crucible/slag interface. The MgO dissolution decreased with the FeO/SiO₂ ratio up to a value of 1.7 and then slightly increased, whereas it continuously increased with the CaO/SiO₂ ratio. There is no obvious relationship between the amount of olivine and the FeO/SiO₂ ratio or CaO/SiO₂ ratio. In comparison, the formation of (Zn,Fe,Mg)O solid solution is enhanced by increasing the FeO/SiO₂ ratio or CaO/SiO₂ ratio in ZFS slags. The results suggest that MgO corrosion is the lowest for FeO/SiO₂ and CaO/SiO₂ ratios around 1.7 and 0, respectively.     

Untersuchungen zur H2O2-Behandlung der Milch II. Mitteilung Einflu? von H2O2 auf Butterfett und einige fettl?sliche Vitamine

Zusammenfassung Milch wird mit Wasserstoffperoxyd in Konzentrationen bis 1% einer 30%igen Lösung versetzt (Einwirkungszeit bis 24 Std bei 30° C oder 1/2 Std bei 51° C) und der Einfluß auf das Butterfett und die fettlöslichen Vitamine untersucht.Unter den angegebenen Bedingungen lassen sich keine oxydativen Veränderungen im Butterfett feststellen. Der Gehalt der Milch an -Carotin, Vitamin A und E wird nicht verändert.Inalkoholischer Lösung sind die Vitamine A und D₃ sowie -Carotin bei H₂O₂-Einwirkung relativ stabil; nur Tokopherol wird schnell zerstört.