2,3,7,8-Tetrachlorodibenzo-p-dioxin alters steroid secretion but does not affect cell viability and the incidence of apoptosis in porcine luteinised granulosa cells

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a by-product of human industrial activity, was found to affect ovarian steroidogenesis in animals, but the mechanism of its action is still unclear. The aims of the study were to examine the effect of TCDD on (1) progesterone (P4) and oestradiol (E2) production by granulosa cells isolated from medium (3–6 mm) and preovulatory (≥ 8 mm) porcine follicles, (2) the viability of the cells, and (3) the incidence of apoptosis. Porcine granulosa cells were cultured (48 h) with or without TCDD (100 pM, 100 nM). Steroid hormone concentrations in the medium were determined by radioimmunoassay. The viability of granulosa cells was tested spectrophotometrically (alamarBlue™ assay). Apoptosis was evaluated by flow cytometry using Annexin V and by TUNEL assay. The higher dose of TCDD (100 nM) significantly inhibited P4 and stimulated E2 production by luteinised granulosa cells isolated from medium follicles. The lower dose of TCDD (100 pM) significantly stimulated P4 and inhibited E2 secretion by the cells isolated from preovulatory follicles. None of the two TCDD doses affected cell viability or induced apoptosis in granulosa cells. In conclusion, TCDD directly affected steroid production by granulosa cells obtained from mature pigs, but the effect of TCDD was not due to its cytotoxicity

Determining the range of influence of tourist trails users on naturally valuable areas : a proposal of a method and a practical example

Purpose: The aim of the article is to present the proprietary methodology for determining the area range of anthropopressure to areas of natural value located along tourist trails and to the entire area where those trails are located. Design/Methodology/Approach: A method of critical analysis of information obtained from various dispersed sources was used to determine the widths of the buffers of the impact of tourists using various types of tourist trails on the environment. Current geodetic and cartographic studies as well as geoportals and thematic websites available on the Internet were used to properly define the course of tourist routes. Spatial analyzes were performed using the ArcGIS software environment. Findings: The results of the research confirm that the proposed simple, cheap and effective methodology allows to take into account many elements of nature and to consider the range of pressure on valuable natural areas as a whole or only on their selected element. It also allows to choose the form of tourist activities in the analyzed area. Practical Implications: The proposed method can be helpful in the management of protected areas, including, for example, the assessment of the tourist capacity of the area and the development of opinions on the creation of new and updating or correction of the existing tourist trails. Originality/Value: Authors presented an algorithm of the most important activities and types of spatial analyzes necessary to identify the extent of the impact of people using various types of tourist trails on naturally valuable areaspeer-reviewe

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience

Background: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. Results: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Effect of the Preparation Method on the Catalytic Properties of Copper-containing Zeolite Y Applied for NH3-SCR-DeNOx

Two series of zeolite Y were prepared with varying particle size (estimated 100 or 400 nm) by applying different synthesis gel composition ratios as well as different ageing and hydrothermal steps. Copper-containing zeolites Y were obtained through ion exchange, thoroughly characterized and tested for the selective catalytic reduction with NH3 (NH3-SCR-DeNOx). The catalytic activity of the prepared materials varied significantly due to the different nature of copper species. Results show that catalysts CuY 0h-A and CuY-24h-A (approx. particles size 2676 and 475 nm, respectively) facilitate a higher NO conversion both in the presence and absence of water vapor, exhibiting however stronger N2O formation above 250 °C. On the other hand, nearly X-ray amorphous Y-0h-B and Y-24h-B after ion- exchange led to decreased activity of CuY-0h-B and CuY-24h-B (approx. particles size 345 and 128 nm, respectively). Additional insight into the activity of both catalyst were obtained through in situ DR UV-Vis spectroscopy

Co-ordination of cell cycle and differentiation in the developing nervous system

During embryonic development, cells must divide to produce appropriate numbers, but later must exit the cell cycle to allow differentiation. How these processes of proliferation and differentiation are co-ordinated during embryonic development has been poorly understood until recently. However, a number of studies have now given an insight into how the cell cycle machinery, including cyclins, CDKs (cyclin-dependent kinases), CDK inhibitors and other cell cycle regulators directly influence mechanisms that control cell fate and differentiation. Conversely, examples are emerging of transcriptional regulators that are better known for their role in driving the differentiated phenotype, which also play complementary roles in controlling cell cycle progression. The present review will summarise our current understanding of the mechanisms co-ordinating the cell cycle and differentiation in the developing nervous system, where these links have been, perhaps, most extensively studied

Healthcare Accessibility and Mortality in 21st Century Russia

This research discusses the underlying causes behind high mortality rates in contemporary Russia. By analyzing various psychological, social, medical, economic, and governmental factors, this research seeks to understand the correlation between Russia’s increasing mortality rates and the overall decline in healthcare accessibility for its citizens. Russia’s mortality rates are significantly higher as compared to other European countries, which suggests that a reevaluation of its healthcare system is necessary. By examining inefficient free medical care, improper allocation of funding, barriers in medical care engagement, substance abuse, and more, this research hopes to offer solutions to a leading problem in contemporary Russia

Biosynthese et maturation des sous-unites alpha et beta de la lutropine (LH) chez le rat : regulation par la gonadoliberine (GnRH)

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc