Improving the precision of forces in real-space pseudopotential density functional theory.

The high-order finite difference real-space pseudopotential density functional theory (DFT) approach is a valuable method for large-scale, massively parallel DFT calculations. A significant challenge in the approach is the oscillating "egg-box" error introduced by aliasing associated with a coarse grid spacing. To address this issue while minimizing computational cost, we developed a finite difference interpolation (FDI) scheme [Roller et al.

Mobile sensing to advance tumor modeling in cancer patients: A conceptual framework.

As mobile and wearable devices continue to grow in popularity, there is strong yet unrealized potential to harness people's mobile sensing data to improve our understanding of their cellular and biologically-based diseases. Breakthrough technical innovations in tumor modeling, such as the three dimensional tumor microenvironment system (TMES), allow researchers to study the behavior of tumor cells in a controlled environment that closely mimics the human body. Although patients' health behaviors are known to impact their tumor growth through circulating hormones (cortisol, melatonin), capturing this process is a challenge to rendering realistic tumor models in the TMES or similar tumor modeling systems.

The Androgen Receptor Does Not Directly Regulate the Transcription of DNA Damage Response Genes.

Unlabelled: The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR).

Finite Difference Interpolation for Reduction of Grid-Related Errors in Real-Space Pseudopotential Density Functional Theory.

The real-space pseudopotential approach is a well-known method for large-scale density functional theory (DFT) calculations. One of its main limitations, however, is the introduction of errors associated with the positioning of the underlying real-space grid, a phenomenon usually known as the "egg-box" effect. The effect can be controlled by using a finer grid, but this raises the cost of the calculations or even undermines their feasibility altogether.

Teleneurocritical care is associated with equivalent billable charges to in-person neurocritical care for patients with acute stroke.

Introduction: Teleneurocritical care (TNCC) provides virtual care for hospitals who do not have continuous neurointensivist coverage. It is not known if TNCC is cost effective nor which variables impact the total billed charges per patient encounter. We characterize cost, defined by charge characteristics of TNCC compared to in-person neurocritical care (NCC), for patients with acute ischemic or hemorrhagic stroke requiring ICU care.

Quality over quantity - development of communicative and social competence in dentistry at the Medical Faculty of Heidelberg.

Given the context of implementing new licensing regulations for dentistry, this project report describes not only the current educational situation regarding communicative and social competency in dental education at the Medical Faculty of Heidelberg, but also introduces supportive and expanded measures that include medical educators and clinical staff. Based on less-than-satisfactory skills acquisition in students and experienced practitioners, it is necesssary to develop communicative and social competence not just in university courses with few hours of instruction, but also to practice and continually improve these skills in an educational clinical setting which serves as a system for teaching and learning knowledge and skills.

Validation of a multicellular tumor microenvironment system for modeling patient tumor biology and drug response.

Lung cancer rates are rising globally and non-small cell lung cancer (NSCLC) has a five year survival rate of only 24%. Unfortunately, the development of drugs to treat cancer is severely hampered by the inefficiency of translating pre-clinical studies into clinical benefit. Thus, we sought to apply a tumor microenvironment system (TMES) to NSCLC.

Role of the runt-related transcription factor (RUNX) family in prostate cancer.

Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in use of AR antagonists and antiandrogen therapies that reduce endogenous steroid hormone production. However, within two to three years of receiving first-line androgen deprivation therapy, the majority of patients diagnosed with PCa progress to castration-resistant prostate cancer (CRPC).

AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR-CHK2 interaction and prostate cancer survival.

We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR) increases this interaction. This IR-induced increase in AR-CHK2 interactions requires AR phosphorylation and CHK2 kinase activity.

Development of a multicellular pancreatic tumor microenvironment system using patient-derived tumor cells.

The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment.

Pregnancy and perinatal conditions and atopic disease prevalence in childhood and adulthood.

Background: Previous studies showed controversial results for the influence of pregnancy-related and perinatal factors on subsequent respiratory and atopic diseases in children. The aim of this study was to assess the association between perinatal variables and the prevalence of asthma, bronchial hyperreactivity (BHR), flexural eczema (FE), allergic rhinitis, and sensitization in childhood and early adulthood.

Methods: The studied population was first examined in Munich and Dresden in 1995/1996 at age 9-11 years.

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas.

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity.

Establishing a birth cohort to investigate the course and aetiology of asthma and allergies across three generations - rationale, design, and methods of the ACROSSOLAR study.

Background: Atopic diseases are a major burden of disease on a global scale. Regarding their aetiology, the early years of life are assumed to play a crucial role. In addition, there is growing evidence that elucidating the impact of cross-generational effects and epigenetic mechanisms such as DNA methylation can substantially widen the scientific knowledge of the occurrence and progression of these diseases.

Systems Analysis of Adaptive Responses to MAP Kinase Pathway Blockade in BRAF Mutant Melanoma.

Fifty percent of cutaneous melanomas are driven by activated BRAFV600E, but tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to mitogen-activated protein kinase (MAPK) pathway inhibition, we identified the combination of PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ErbB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720.

Predictors of work-related sensitisation, allergic rhinitis and asthma in early work life.

Although work-related asthma and allergies are a huge burden for society, investigation of occupational exposures in early work life using an unexposed reference group is rare. Thus, the present analyses aimed to assess the potential impact of occupational exposure and other risk factors on the prevalence of work-related sensitisation and incidence of allergic rhinitis/asthma using a population-based approach and taking into account an unexposed reference group. In SOLAR (Study on Occupational Allergy Risks) II, German participants of ISAAC (International Study of Asthma and Allergies in Childhood) phase II were followed from childhood (9-11 years) until early adulthood (19-24 years).

Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.

Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks.

Role of the UL45 protein in herpes simplex virus entry via low pH-dependent endocytosis and its relationship to the conformation and function of glycoprotein B.

Herpesviruses commandeer distinct cellular pathways to enter target cells. The mechanism by which herpes simplex virus (HSV) selects a pH-dependent, endocytic route or a pH-independent route remains to be elucidated. We investigated the role of the non-glycosylated viral envelope protein UL45 in HSV entry via endocytosis.

Clinical impact of early hyperglycemia during acute phase of traumatic brain injury.

Introduction: While tight glucose control has been widely adopted in the critical care setting, the optimal target glucose level following acute traumatic brain injury (TBI) remains debatable. This observational study was conducted to delineate the relationship between glucose levels and clinical outcomes during acute phase (first 5 days) of TBI.

Methods: We retrospectively identified 429 TBI patients admitted to the intensive care unit (ICU) from January 2005 to December 2006.

Structure-function analysis of herpes simplex virus glycoprotein B with fusion-from-without activity.

Fusion-from-without (FFWO) is the rapid induction of cell fusion by virions in the absence of viral protein synthesis. The combination of two amino acid mutations in envelope glycoprotein B (gB), one in the ectodomain and one in the cytoplasmic tail, can confer FFWO activity to wild type herpes simplex virus (HSV). In this report, we analyzed the entry and cell fusion phenotypes of HSV that contains FFWO gB, with emphasis on the cellular receptors for HSV, nectin-1, nectin-2 and HVEM.

Cellular proteasome activity facilitates herpes simplex virus entry at a postpenetration step.

Herpes simplex virus (HSV) entry into cells is a multistep process that engages the host cell machinery. The proteasome is a large, ATP-dependent, multisubunit protease that plays a critical role in the maintenance of cell homeostasis. A battery of assays were used to demonstrate that proteasome inhibitors blocked an early step in HSV entry that occurred after capsid penetration into the cytosol but prior to capsid arrival at the nuclear periphery.

Opto-electronic DNA chip-based integrated card for clinical diagnostics.

Clinical diagnostics is one of the most promising applications for microfluidic lab-on-a-chip or lab-on-card systems. DNA chips, which provide multiparametric data, are privileged tools for genomic analysis. However, automation of molecular biology protocol and use of these DNA chips in fully integrated systems remains a great challenge.