Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines

The effect of urban green spaces on house prices in Warsaw

In the paper, we analysed the impact of proximity to urban green areas on apartment prices in Warsaw. The data-set contained in 43 075 geo-coded apartment transactions for the years 2010 to 2015. In this research, the hedonic method was used in Ordinary Least Squares (OLS), Weighted Least Squares (WLS) and Median Quantile Regression (Median QR) models. We found substantial evidence that proximity to an urban green area is positively linked with apartment prices. On an average presence of a green area within 100 meters from an apartment increases the price of a dwelling by 2,8% to 3,1%. The effect of park/forest proximity on house prices is more significant for newer apartments than those built before 1989. We found that proximity to a park or a forest is particularly important (and has a higher implicit price as a result) in the case of buildings constructed after 1989. The impact of an urban green was particularly high in the case of a post-transformation housing estate. Close vicinity (less than 100 m distance) to an urban green increased the sales prices of apartments in new residential buildings by 8,0–8,6%, depending on a model

Development of chronic bronchitis and emphysema in β-epithelial Na+ channel-overexpressing mice

Rationale: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in β-epithelial Na+ channel (βENaC)-overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors. Objectives: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration. Methods: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in βENaC-overexpressing mice. Measurements and Main Results: Mucus obstruction in βENaC- overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving βENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-α and macrophages, IL-13 and eosinophils, and persistent increases inkeratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. βENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance. Conclusions: Our studies demonstrate that airway surface dehydration is sufficient toinitiatepersistentneutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies

Inertial displacement of a domain wall excited by ultra-short circularly polarized laser pulses.

Domain wall motion driven by ultra-short laser pulses is a pre-requisite for envisaged low-power spintronics combining storage of information in magnetoelectronic devices with high speed and long distance transmission of information encoded in circularly polarized light. Here we demonstrate the conversion of the circular polarization of incident femtosecond laser pulses into inertial displacement of a domain wall in a ferromagnetic semiconductor. In our study, we combine electrical measurements and magneto-optical imaging of the domain wall displacement with micromagnetic simulations. The optical spin-transfer torque acts over a picosecond recombination time of the spin-polarized photo-carriers that only leads to a deformation of the initial domain wall structure. We show that subsequent depinning and micrometre-distance displacement without an applied magnetic field or any other external stimuli can only occur due to the inertia of the domain wall

Prevalence of JC Virus in Chinese Patients with Colorectal Cancer

BACKGROUND: JCV is a DNA polyomavirus very well adapted to humans. Although JCV DNA has been detected in colorectal cancers (CRC), the association between JCV and CRC remains controversial. In China, the presence of JCV infection in CRC patients has not been reported. Here, we investigated JCV infection and viral DNA load in Chinese CRC patients and to determine whether the JCV DNA in peripheral blood (PB) can be used as a diagnostic marker for JCV-related CRC. METHODOLOGY/PRINCIPAL FINDINGS: Tumor tissues, non-cancerous tumor-adjacent tissues and PB samples were collected from 137 CRC patients. In addition, 80 normal colorectal tissue samples from patients without CRC and PB samples from 100 healthy volunteers were also harvested as controls. JCV DNA was detected by nested PCR and glass slide-based dot blotting. Viral DNA load of positive samples were determined by quantitative real-time PCR. JCV DNA was detected in 40.9% (56/137) of CRC tissues at a viral load of 49.1 to 10.3×10(4) copies/µg DNA. Thirty-four (24.5%) non-cancerous colorectal tissues (192.9 to 4.4×10(3) copies/µg DNA) and 25 (18.2%) PB samples (81.3 to 4.9×10(3) copies/µg DNA) from CRC patients were positive for JCV. Tumor tissues had higher levels of JCV than non-cancerous tissues (P = 0.003) or PB samples (P<0.001). No correlation between the presence of JCV and demographic or medical characteristics was observed. The JCV prevalence in PB samples was significantly associated with the JCV status in tissue samples (P<0.001). Eleven (13.8%) normal colorectal tissues and seven (7.0%) PB samples from healthy donors were positive for JCV. CONCLUSIONS/SIGNIFICANCE: JCV infection is frequently present in colorectal tumor tissues of CRC patients. Although the association between JCV presence in PB samples and JCV status in tissue samples was identified in this study, whether PB JCV detection can serve as a marker for JCV status of CRC requires further study

Hypoxic Epithelial Necrosis Triggers Neutrophilic Inflammation via IL-1 Receptor Signaling in Cystic Fibrosis Lung Disease

Rationale: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease

FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas

Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) in the same samples. The frequency of FasL detection was 30–40% in T and was 60–100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasL-induced apoptosis or other hitherto unknown mechanisms. © 1999 Cancer Research Campaig

Experimental concepts for toxicity prevention and tissue restoration after central nervous system irradiation

Several experimental strategies of radiation-induced central nervous system toxicity prevention have recently resulted in encouraging data. The present review summarizes the background for this research and the treatment results. It extends to the perspectives of tissue regeneration strategies, based for example on stem and progenitor cells. Preliminary data suggest a scenario with individually tailored strategies where patients with certain types of comorbidity, resulting in impaired regeneration reserve capacity, might be considered for toxicity prevention, while others might be "salvaged" by delayed interventions that circumvent the problem of normal tissue specificity. Given the complexity of radiation-induced changes, single target interventions might not suffice. Future interventions might vary with patient age, elapsed time from radiotherapy and toxicity type. Potential components include several drugs that interact with neurodegeneration, cell transplantation (into the CNS itself, the blood stream, or both) and creation of reparative signals and a permissive microenvironment, e.g., for cell homing. Without manipulation of the stem cell niche either by cell transfection or addition of appropriate chemokines and growth factors and by providing normal perfusion of the affected region, durable success of such cell-based approaches is hard to imagine

Organization and training at national level of antimicrobial stewardship and infection control activities in Europe: an ESCMID cross-sectional survey

Antimicrobial stewardship (AMS) and Infection prevention and control (IPC) are two key complementary strategies that combat development and spread of antimicrobial resistance. The ESGAP (ESCMID Study Group for AMS), EUCIC (European Committee on Infection Control) and TAE (Trainee Association of ESCMID) investigated how AMS and IPC activities and training are organized, if present, at national level in Europe. From February 2018 to May 2018, an internet-based cross-sectional survey was conducted through a 36-item questionnaire, involving up to three selected respondents per country, from 38 European countries in total (including Israel), belonging to the ESGAP/EUCIC/TAE networks. All 38 countries participated with at least one respondent, and a total of 81 respondents. Education and involvement in AMS programmes were mandatory during the postgraduate training of clinical microbiology and infectious diseases specialists in up to one-third of countries. IPC was acknowledged as a specialty in 32% of countries. Only 32% of countries had both guidance and national requirements regarding AMS programmes, in contrast to 61% for IPC. Formal national staffing standards for AMS and IPC hospital-based activities were present in 24% and 63% of countries, respectively. The backgrounds of professionals responsible for AMS and IPC programmes varied tremendously between countries. The organization and training of AMS and IPC in Europe are heterogeneous and national requirements for activities are frequently lacking