Improved pharmacokinetics and tissue uptake of complexed daidzein in rats

The pharmacokinetic profile and tissue uptake of daidzein (DAI) was determined in rat serum and tissues (lungs, eyes, brain, heart, spleen, fat, liver, kidney, and testes) after intravenous and intraperitoneal administration of DAI in suspension or complexed with ethylenediamine-modified γ-cyclodextrin (GCD-EDA/DAI). The absolute and relative bioavailability of DAI suspended (20 mg/kg i.v. vs. 50 mg/kg i.p.) and complexed (0.54 mg/kg i.v. vs. 1.35 mg/kg i.p.) was determined. After i.p. administration, absorption of DAI complexed with GCD-EDA was more rapid (tmax = 15 min) than that of DAI in suspension (tmax = 45 min) with a ca. 3.6 times higher maximum concentration (Cmax = 615 vs. 173 ng/mL). The i.v. half-life of DAI was longer in GCD-EDA/DAI complex compared with DAI in suspension (t0.5 = 380 min vs. 230 min). The volume of distribution of DAI given i.v. in GCD-EDA/DAI complex was ca. 6 times larger than DAI in suspension (38.6 L/kg vs. 6.2 L/kg). Our data support the concept that the pharmacokinetics of DAI suspended in high doses are nonlinear. Increasing the intravenous dose 34 times resulted in a 5-fold increase in AUC. In turn, increasing the intraperitoneal dose 37 times resulted in a ca. 2-fold increase in AUC. The results of this study suggested that GCD-EDA complex may improve DAI bioavailability after i.p. administration. The absolute bioavailability of DAI in GCD-EDA inclusion complex was ca. 3 times greater (F = 82.4% vs. 28.2%), and the relative bioavailability was ca. 21 times higher than that of DAI in suspension, indicating the need to study DAI bioavailability after administration by routes other than intraperitoneal, e.g., orally, subcutaneously, or intramuscularly. The concentration of DAI released from GCD-EDA/DAI inclusion complex to all the rat tissues studied was higher than after administration of DAI in suspension. The concentration of DAI in brain and lungs was found to be almost 90 and 45 times higher, respectively, when administered in complex compared to the suspended DAI. Given the nonlinear relationship between DAI bioavailability and the dose released from the GCD-EDA complex, complexation of DAI may thus offer an effective approach to improve DAI delivery for treatment purposes, for example in mucopolysaccharidosis (MPS), allowing the reduction of ingested DAI doses

Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted

Measurement of the very rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu decay

The decay K+→π+νν¯ , with a very precisely predicted branching ratio of less than 10−10 , is among the best processes to reveal indirect effects of new physics. The NA62 experiment at CERN SPS is designed to study the K+→π+νν¯ decay and to measure its branching ratio using a decay-in-flight technique. NA62 took data in 2016, 2017 and 2018, reaching the sensitivity of the Standard Model for the K+→π+νν¯ decay by the analysis of the 2016 and 2017 data, and providing the most precise measurement of the branching ratio to date by the analysis of the 2018 data. This measurement is also used to set limits on BR(K+→π+X ), where X is a scalar or pseudo-scalar particle. The final result of the BR(K+→π+νν¯ ) measurement and its interpretation in terms of the K+→π+X decay from the analysis of the full 2016-2018 data set is presented, and future plans and prospects are reviewed

Spectrometer and Kinematic Studies for New Physics Searches in Rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu Decay at NA62 Experiment at CERN

The main focus of the presented thesis is twofold: First the STRAW spectrometer single track reconstruction efficiency evaluation carried out with $K^+ \to \pi^+ \pi^0$, $K^+ \to \pi^0 \mu^+ \nu$ and $K^+ \to \pi^0 e^+ \nu$ samples on the full 2016-2018 NA62 data set as well as on simulated decays is summarized. Secondly a new algorithm for matching kaon candidates with $\pi^+$ tracks based on likelihood hypothesis testing is proposed. Performance of the algorithm is studied with fully reconstructed $K^+ \to \pi^+ \pi^+ \pi^-$ event candidates and results of a part of the $K^+ \to \pi^+ \nu \overline{\nu}$ analysis with the new matching algorithm with the 2017 data sample are presented

Recent results in kaon physics

A review of the present experimental status of the $K \to \pi \nu \overline{\nu}$ ($K_{\pi \nu \nu}$) and other kaon decay analyses at experiments NA62 (CERN) and KOTO (J-PARC) is given. The $K_{\pi \nu \nu}$ decay is one of the best candidates among the rare meson decays for indirect searches for new physics in the mass ranges complementary to those accessible by current accelerators. The Standard Model (SM) prediction of the branching fraction ($\mathcal{B}$) of the $K_{\pi \nu \nu}$ decay is lower than $10^{-10}$ in both neutral and charged modes. The NA62 experiment aims to measure the $\mathcal{B}$ of the charged mode with better than 10\% precision. Three candidate events, compatible with the SM prediction, have been observed from a sample of 2.12$\times 10^{12}$ $K^+$ decays collected in 2016 and 2017 by NA62. More than twice the statistics is available in the 2018 dataset currently being analysed. The KOTO experiment in Japan aims to measure $\mathcal{B}$($K_L \to \pi^0 \nu \overline{\nu}$) using a technique similar to NA62, but with much lower momentum. In the first dataset taken in 2015 zero signal candidate events were observed. The current status of the analysis of the 2016-2018 dataset with 1.4 times more data is presented.Finally, the most recent results of other physics analyses at the NA62 experiment are summarised

Systematic study of physics biases caused by different multiplicity estimators

Systematic study of physics biases caused by different multiplicity estimators in pp collisions was done by analyzing pseudorapidity distributions and $p_{t}$ spectra. Analysis was done in several steps. The analysis was done in several steps. First we found pseudorapidity distributions in different $\eta$ ranges and given centrality classes. For this purpose both real data and Monte Carlo events were used.\nIn next steps we worked only with MC pp events. We analysed $p_{t}$ spectra of four different particle species from most central events. Finally we used the Blast-wave model to fit these spectra

Managing service quality in retail banking : from branch to multi-channel distribution

International audience

Listeriosis Outbreaks Associated with Soft Cheeses, United States, 1998–2014

Since 2006, the number of reported US listeriosis outbreaks associated with cheese made under unsanitary conditions has increased. Two-thirds were linked to Latin-style soft cheese, often affecting pregnant Hispanic women and their newborns. Adherence to pasteurization protocols and sanitation measures to avoid contamination after pasteurization can reduce future outbreaks

ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells

Abstract Background Efficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma. Methods Chemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice. Results The prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC50 value for 5-fluorouracil in comparison to parental counterparts HT-29/EGFP. The capability of chemoresistant cells to form tumor xenografts, when injected subcutaneously into SCID/bg mice, was strongly compromised, however, they formed distant metastases in mouse lungs spontaneously. Derived cells preserved their resistance in vitro and in vivo even without the 5-fluorouracil selection pressure. More importantly, they were resistant to cisplatin, oxaliplatin and cyclophosphamide exhibiting high cross-resistance along with alterations in expression of cancer-stem cell markers such as CD133, CD166, CD24, CD26, CXCR4, CD271 and CD274. We also detected increased aldehyde dehydrogenase (ALDH) activity associated with overexpression of specific ALDH isoform 1A3. Its inhibition by siRNA approach partially sensitized cells to various agents, thus linking for the first time the ALDH1A3 and chemoresistance in colorectal cancer. Conclusion Our study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination