Homogeneous Bubble Nucleation driven by local hot spots: a Molecular Dynamics Study

We report a Molecular Dynamics study of homogenous bubble nucleation in a Lennard-Jones fluid. The rate of bubble nucleation is estimated using forward-flux sampling (FFS). We find that cavitation starts with compact bubbles rather than with ramified structures as had been suggested by Shen and Debenedetti (J. Chem. Phys. 111:3581, 1999). Our estimate of the bubble-nucleation rate is higher than predicted on the basis of Classical Nucleation Theory (CNT). Our simulations show that local temperature fluctuations correlate strongly with subsequent bubble formation - this mechanism is not taken into account in CNT

Transcriptional Repressive H3K9 and H3K27 Methylations Contribute to DNMT1-Mediated DNA Methylation Recovery

DNA methylation and histone modifications are two major epigenetic events regulating gene expression and chromatin structure, and their alterations are linked to human carcinogenesis. DNA methylation plays an important role in tumor suppressor gene inactivation, and can be revised by DNA methylation inhibitors. The reversible nature of DNA methylation forms the basis of epigenetic cancer therapy. However, it has been reported that DNA re-methylation and gene re-silencing could occur after removal of demethylation treatment and this may significantly hamper the therapeutic value of DNA methylation inhibitors. In this study we have provided detailed evidence demonstrating that mammalian cells possess a bona fide DNA methylation recovery system. We have also shown that DNA methylation recovery was mediated by the major human DNA methyltransferase, DNMT1. In addition, we found that H3K9-tri-methylation and H3K27-tri-methylation were closely associated with this DNA methylation recovery. These persistent transcriptional repressive histone modifications may have a crucial role in regulating DNMT1-mediated DNA methylation recovery. Our findings may have important implications towards a better understanding of epigenetic regulation and future development of epigenetic therapeutic intervention

Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy

A Europe-wide inventory of citizen-led energy action with data from 29 countries and over 10000 initiatives

Numerous case studies show that citizens engage in various ways in renewable and low carbon energy projects, thereby contributing to the sustainable energy transition. To date, however, a systematic and cross-country database on citizen-led initiatives and projects is lacking. By performing a major compilation and reviewing copious data sources from websites to official registries, we provide a Europe-wide inventory with over 10,000 initiatives and 16,000 production units in 29 countries, focusing on the past 20 years. Our data allow cross-country statistical analysis, supporting the elicitation of empirical insights capable of extending beyond the perspective of single case studies. Our data also align with ongoing efforts to implement two EU Directives that aim at strengthening the active role of citizens in the energy transition. While the focus of our data collection is on Europe, the data and methodology can contribute to the global analysis of citizen-led energy action

Radiosensitivity of Prostate Cancer and BPH Patients Studied by DNA Repair Capacity, CA and FISH.

An individuals genetic constitution and lifestyle, e.g., diet and levels of physical activity, can affect the bodys response to various exogenous agents including therapeutic treatment. There is a strong need to combine studies on variability in a cellular response to genotoxic exposure with predisposition of the patient to diseases development and healing. In this study a variation in responses to challenging dose of X rays in lymphocytes from healthy donors and prostate cancer patients were compared on the molecular and mitotic levels. Blood was collected from healthy donors BPH (Benign Prostate Hyperplasia), and prostate cancer patients. Among cancer patients 33% never smoke 46.7% were former smokers. Immediately after collecting the blood a challenging irradiation was performed followed by culturing procedures for classic cytogenetics and FISH techniques with a probe for the whole chromosome 1. In DNA damage investigations, isolated and cryopreserved lymphocytes were thawed and their viability examined before molecular studies. To evaluate individual susceptibility, defrosted lymphocytes were exposed to 4 Gy dose of X-rays and the extent of DNA damage was studied right after irradiation with the alkaline version of the single cell gel electrophoresis (SCGE) assay. To asses variability in the DNA repair competency the residual (unrepaired) DNA damage was detected again after one hour of incubation, during which irradiated cells had the condition allowing to complete the fast DNA repair process. Visible difference between DNA susceptibilities to the challenging dose was observed between investigated groups. However, variation between individuals in repair efficiency of the DNA damage induced by the challenging treatment was significantly higher in lymphocytes of prostate cancer patients than that of BPH and healthy donors (p<.05). That findings correlate with results from cytogenetic studies. Significantly higher amount of chromosomal damage was detected in irradiated lymphocytes of prostate cancer than that in BPH patients by classic cytogenetics. Results obtained by FISH technique have also shown a statistically significantly higher level of translocations frequency (4.3 ± 0.33 vs 2.9 ± 0.31, p<.005) in chromosome 1 of prostate cancer lymphocytes than that of BPH. Our results, clearly suggest that vulnerability of chromosome 1 and DNA repair competence assays have shown a possible potency as predictive assays in preclinical studies. *the MSC foundation fellow from Kazakh National University, Almaty, Kazakhsta