Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.     

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.     

Betula alba Bark Extract and Empetrum nigrum Fruit Juice,a Natural Alternative to Niacinamide for Skin Barrier Benefits

The Scandinavian region is home to a unique biome with endemic plant species. The aim of this study was to explore this natural diversity and identify plant extracts providing positive skin barrier effects. Six plant extracts were identified as starting material. Following biochemical screening, two candidates outperformed the rest: Betula alba (BA) and Empetrum nigrum (EN). Quantitative PCR analysis showed that BA and EN upregulated barrier genes, when used individually and in combination. Betula alba increased AQP3 and OCLN protein expression, something niacinamide was incapable of. Additionally, the skin barrier was strengthened, evidenced by inhibition of KLK5 and hyaluronidase and showed strong antioxidant and anti-inflammatory activity through DPPH and COX2 inhibition, respectively. A first split-face clinical study was conducted using the combination of extracts versus placebo. There was a significantly better skin restructuring effect and corneocyte cohesion on the side treated with combined extracts. A second split-face clinical study assessed the combined extracts versus 3% niacinamide. Significant variations in skin hydration and TEWL were observed in favor of the extract treated side. In conclusion, we identified a natural alternative to niacinamide for improving skin barrier health, in Scandinavian plant extracts, which yield strong performance, but at a lower concentration.     

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).     

Five-year experience with setup and implementation of an integrated database system for clinical documentation and research

In radiation oncology, where treatment concepts are elaborated in interdisciplinary collaborations, handling distributed, large heterogeneous amounts of data efficiently is very important, yet challenging, for an optimal treatment of the patient as well as for research itself. This becomes a strong focus, as we step into the era of modern personalized medicine, relying on various quantitative data information, thus involving the active contribution of multiple medical specialties. Hence, combining patient data from all involved information systems is inevitable for analyses. Therefore, we introduced a documentation and data management system integrated in the clinical environment for electronic data capture. We discuss our concept and five-year experience of a precise electronic documentation system, with special focus on the challenges we encountered. We specify how such a system can be designed and implemented to plan, tailor and conduct (multicenter) clinical trials, ultimately reaching the best clinical performance, and enhancing interdisciplinary and clinical research.     

Are financial incentives related to performance? A meta-analytic review of empirical research.

The relationship of financial incentives to performance quality and quantity is cumulated over 39 studies containing 47 relationships. Financial incentives were not related to performance quality but had a corrected correlation of .34 with performance quantity. Setting (laboratory, field, experimental simulation) and theoretical framework moderated the relationship, but task type did not. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Empirical and Conceptual Problems With Longitudinal Trait-State Models: Introducing a Trait-State-Occasion Model.

The latent trait-state-error model (TSE) and the latent state-trait model with autoregression (LST-AR) represent creative structural equation methods for examining the longitudinal structure of psychological constructs. Application of these models has been somewhat limited by empirical or conceptual problems. In the present study, Monte Carlo analysis revealed that TSE models tend to generate improper solutions when N is too small, when waves are too few, and when occasion factor stability is either too large or too small. Mathematical analysis of the LST-AR model revealed its limitation to constructs that become more highly auto-correlated over time. The trait-state-occasion model has fewer empirical problems than does the TSE model and is more broadly applicable than is the LST-AR model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

‘The crystal structure problem’ in noble gas nanoclusters

Calculations of the energetics of multiply twinned particles (MTPs) such as icosahedra and decahedra with fivefold symmetry as well as face-centered cubic (fcc) and hexagonal close-packed (hcp) particles in the size interval from 13 up to ∼ 45,000 atoms were made applying Lennard-Jones potentials. We essentially extended the size interval comparatively with previous studies and included shape-optimized hcp clusters in the global energy analysis that gives rise to the new insight into the basic fcc/hcp problem. For the cluster size N from minimal up to N ∼ 2000 atoms the binding energy is highest for icosahedra, in the size interval from 2000 up to ∼ 11,500 atoms decahedra prevail, above N ∼ 11,500 atoms decahedra and optimized fcc clusters were found to alternate. The hcp structure was revealed to become favorable above N ∼ 34,000 atoms. Thus, hcp clusters can attain their preference with respect to MTPs (comprising fcc fragments) and optimized fcc clusters only for very large sizes. The comparison with several other models is suggested and the opportunity of experimental observations is discussed.     

Social comparison between young children in achievement situations.

Examined the development of children's motivations to socially compare in a situation in which they were free to seek or not seek information about how another child was doing. 16 males and 16 females each at the kindergarten, 1st, and 2nd grade levels were recruited through the newspaper and paid to participate. Pairs of Ss in the same grade worked on a speed task under high- and low-competition conditions. The frequency and duration with which Ss pushed a button to observe their partner's progress on a monitor was the index of the strength of motivation. Results show the expected developmental increase in comparison behavior. Only in 2nd graders did the expected positive relationship between level of competition and performance appear. At the kindergarten level, the means were in the opposite direction, while for the 1st-grade level the relation between competition and performance depended on sex. Results are discussed in terms of alternative predictions derived from theories by L. Festinger (1954) and J. Veroff (1969). (PsycINFO Database Record (c) 2010 APA, all rights reserved)