Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D₃ metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)₂D₃ analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.     

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (T_regs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.     

Poly(chitosan-ester-ether-urethane) Hydrogels as Highly Controlled Genistein Release Systems

Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) hydrogels and to study the kinetic release of genistein (GEN) from these biomaterials. In view of the above, six non-toxic hydrogels were synthesized via the Ring-Opening Polymerization (ROP) and polyaddition processes. The poly(ester-ether) components of the hydrogels have been produced in the presence of the enzyme as a biocatalyst. In some cases, the in vitro release rate of GEN from the obtained hydrogels was characterized by near-zero-order kinetics, without “burst release” and with non-Fickian transport. It is important to note that developed hydrogels have been shown to possess the desired safety profile due to lack of cytotoxicity to skin cells (keratinocytes and fibroblasts). Taking into account the non-toxicity of hydrogels and the relatively highly controlled release profile of GEN, these results may provide fresh insight into polymeric hydrogels as an effective dermatological and/or cosmetological tool.     

Optimal correlation attack on the multiplexer generator

The security of the well-known multiplexer generator with respect to correlation attacks on the data shift register is investigated. Apart from the basic correlation attack exploiting the bitwise correlation between the output sequence and any data input sequence, two new correlation attacks are introduced. One is based on computing the a posteriori probabilities and is statistically optimal, whereas the other makes use of the accumulated bitwise correlation to all data input sequences. It is theoretically argued and experimentally confirmed that the optimal attack requires a significantly shorter output sequence to be successful than the basic attack. The experiments also show that the less complex accumulated correlation attack requires a somewhat longer output sequence than the optimal attack.     

Experimental study on the effect of nanosized carbon particles on fatigue resistance of asphalt binders

The present research study investigates the fatigue resistance of asphalt binders modified with carbon nanoparticles. Three different modified bitumens containing three different dosages of carbon nanoparticles were tested to capture fatigue properties under the concept of viscoelastic continuum damage mechanics through frequency sweep and linear amplitude sweep tests. Results show that adding carbon nanoparticles can enhance the fatigue life of neat asphalt binders.     

Rheological characteristics of oligomeric semiproducts gained via chemical degradation of polyurethane foam using crude glycerin in the presence of different catalysts

Polyurethane (PU) recycling is a topic of growing interest due to the increasing amount of polyurethane waste. The main purpose of polyurethane chemical recycling is to recover the starting polyol. In this study, a method of polyurethane thermochemical recycling, glycerolysis by means of crude glycerin, is proposed. This work presents a comparative study of commercial catalysts used in order to accelerate the decomposition process, namely triethylamine (TEA), potassium acetate (KAc), 1,4‐diazabicyclo[2.2.2]octane (DABCO), sodium hydroxide (NaOH), dibutyltin dilaurate (DbDl), and stannous octoate (StOc).The effect of used catalyst on the chemical structure and rheological properties was studied. The type of catalyst does not have significant influence on the chemical structure, but causes different course of reaction: split‐ and single‐phase in applied conditions. Glycerolysates were measured by Brookfield Rheometer. It was found that repolyols can be described by the Herschel–Bulkely mathematical model in the best accuracy. The investigation showed that the rheological behavior of glycerolysates depended on the catalyst used in glycerolysis process. POLYM. ENG. SCI., 57:891–900, 2017. © 2016 Society of Plastics Engineers     

Insulating and Other Physical Properties of CoO‐Doped Zinc Oxyfluoride‐Borate Glass‐Ceramics

Zinc oxy fluoro borate glasses mixed with different concentrations of CoO (ranging from 0 to 2.0 mol%) are synthesized and subsequently crystallized. The scanning electron microscopy pictures have exhibited crystallinity. Differential scanning calorimetric studies have indicated that the prepared samples consist of multiple crystal phases. The X‐ray diffraction patterns have indicated that the glass‐ceramic samples are composed of αZn(BO₂)_2, (Zn)₃(BO₃)_2, CoF₂, CoF₃, Co₃FB₇O₁₃, ZnCo₂O₄, Co₃O₄ crystalline phases. The optical absorption and photoluminescence studies have indicated that there is a gradual increase of tetrahedral cobalt ion concentration with increase of CoO concentration in the glass network. IR spectroscopic studies have pointed out increased degree of polymerization of the zinc oxy fluoro borate glass network with increase of CoO content. The analysis of results of dielectric properties indicated increase of insulating strength of the glass‐ceramics with increase of CoO content. Finally, the dielectric breakdown strength of the samples is measured at room temperature in air medium and it is found to increase from 12.9 to 19.2 kV/cm with increase of CoO from 0.2 to 2.0 mol%. The reasons for such increase of breakdown strength are discussed quantitatively in terms of dielectric parameters with aid of data on spectroscopic properties.     

Long-Term Changes in Ovarian Follicles of Gilts Exposed Neonatally to Methoxychlor: Effects on Oocyte-Derived Factors,Anti-Müllerian Hormone,Follicle-Stimulating Hormone,and Cognate Receptors

In this paper, we investigated the effects of neonatal exposure to methoxychlor (MXC), a synthetic organochlorine used as an insecticide with estrogenic, antiestrogenic, and antiandrogenic activities on ovarian follicles of adult pigs. Piglets were injected with MXC (20 μg/kg body weight) or corn oil (controls) from postnatal Day 1 to Day 10 (n = 5 per group). Then, mRNA expression, protein abundance and immunolocalization of growth and differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), anti-Müllerian hormone (AMH) and cognate receptors (ACVR1, BMPR1A, BMPR1B, TGFBR1, BMPR2, and AMHR2), as well as FSH receptor (FSHR) were examined in preantral and small antral ovarian follicles of sexually mature gilts. The plasma AMH and FSH levels were also assessed. In preantral follicles, neonatal exposure to MXC increased GDF9, BMPR1B, TGFBR1, and BMPR2 mRNAs, while the levels of AMH and BMP15 mRNAs decreased. In addition, MXC also decreased BMP15 and BMPR1B protein abundance. Regarding small antral follicles, neonatal exposure to MXC upregulated mRNAs for BMPR1B, BMPR2, and AMHR2 and downregulated mRNAs for AMH, BMPR1A, and FSHR. MXC decreased the protein abundance of AMH, and all examined receptors in small antral follicles. GDF9 and BMP15 were immunolocalized in oocytes and granulosa cells of preantral follicles of control and treated ovaries. All analyzed receptors were detected in the oocytes and granulosa cells of preantral follicles, and in the granulosa and theca cells of small antral follicles. The exception, however, was FSHR, which was detected only in the granulosa cells of small antral follicles. In addition, MXC decreased the plasma AMH and FSH concentrations. In conclusion, the present study may indicate long-term effects of neonatal MXC exposure on GDF9, BMP15, AMH, and FSH signaling in ovaries of adult pigs. However, the MXC effects varied at different stages of follicular development. It seems that neonatal MXC exposure may result in accelerated initial recruitment of ovarian follicles and impaired cyclic recruitment of antral follicles.     

Modulatory Effects of Biosynthesized Gold Nanoparticles Conjugated with Curcumin and Paclitaxel on Tumorigenesis and Metastatic Pathways—In Vitro and In Vivo Studies

Background: Breast cancer is the most common cancer in women globally, and diagnosing it early and finding potential drug candidates against multi-drug resistant metastatic breast cancers provide the possibilities of better treatment and extending life. Methods: The current study aimed to evaluate the synergistic anti-metastatic activity of Curcumin (Cur) and Paclitaxel (Pacli) individually, the combination of Curcumin–Paclitaxel (CP), and also in conjugation with gold nanoparticles (AuNP–Curcumin (Au-C), AuNP–Paclitaxel (Au-P), and AuNP–Curcumin–Paclitaxel (Au-CP)) in various in vitro and in vivo models. Results: The results from combination treatments of CP and Au-CP demonstrated excellent synergistic cytotoxic effects in triple-negative breast cancer cell lines (MDA MB 231 and 4T1) in in vitro and in vivo mouse models. Detailed mechanistic studies were performed that reveal that the anti-cancer effects were associated with the downregulation of the expression of VEGF, CYCLIN-D1, and STAT-3 genes and upregulation of the apoptotic Caspase-9 gene. The group of mice that received CP combination therapy (with and without gold nanoparticles) showed a significant reduction in the size of tumor when compared to the Pacli alone treatment and control groups. Conclusions: Together, the results suggest that the delivery of gold conjugated Au-CP formulations may help in modulating the outcomes of chemotherapy. The present study is well supported with observations from cell-based assays, molecular and histopathological analyses.