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Pancreatic cancer is a fatal malignancy with poor prognosis and limited treatment options. Early detection in primary and secondary locations is critical, but fraught with challenges. While digital pathology can assist with the classification of histopathological images, the training of such networks always relies on a ground truth, which is frequently compromised as tissue sections contain several types of tissue entities. Here we show that pancreatic cancer can be detected on hematoxylin and eosin (H&E) sections by convolutional neural networks using deep transfer learning. To improve the ground truth, we describe a preprocessing data clean-up process using two communicators that were generated through existing and new datasets. Specifically, the communicators moved image tiles containing adipose tissue and background to a new data class. Hence, the original dataset exhibited improved labeling and, consequently, a higher ground truth accuracy. Deep transfer learning of a ResNet18 network resulted in a five-class accuracy of about 94% on test data images. The network was validated with independent tissue sections composed of healthy pancreatic tissue, pancreatic ductal adenocarcinoma, and pancreatic cancer lymph node metastases. The screening of different models and hyperparameter fine tuning were performed to optimize the performance with the independent tissue sections. Taken together, we introduce a step of data preprocessing via communicators as a means of improving the ground truth during deep transfer learning and hyperparameter tuning to identify pancreatic ductal adenocarcinoma primary tumors and metastases in histological tissue sections.

Simulations of cosmic evolution are a means to explain the formation of the universe as we see it today. The resulting data of such simulations comprise numerous physical quantities, which turns their analysis into a complex task. Here, we analyze such high-dimensional and time-varying particle data using various visualization techniques from the fields of particle visualization, flow visualization, volume visualization, and information visualization. Our approach employs specialized filters to extract and highlight the development of so-called active galactic nuclei and filament structures formed by the particles. Additionally, we calculate X-ray emission of the evolving structures in a preprocessing step to complement visual analysis. Our approach is integrated into a single visual analytics framework to allow for analysis of star formation at interactive frame rates. Finally, we lay out the methodological aspects of our work that led to success at the 2019 IEEE SciVis Contest.

We assess the impact of exogenous variation in oral contraceptives prices-a year-long decline followed by a sharp increase due to a documented collusion case-on fertility decisions and newborns' outcomes. Our empirical strategy follows an interrupted time-series design, which is implemented using multiple sources of administrative information. As prices skyrocketed (45% within a few weeks), the Pill's consumption plunged, and weekly conceptions increased (3.2% after a few months). We show large effects on the number of children born to unmarried mothers, to mothers in their early twenties, and to primiparae women. The incidence of low birth weight and fetal/infant deaths increased (declined) as the cost of birth control pills rose (fell). In addition, we document a disproportional increase in the weekly miscarriage and stillbirth rates. As children reached school age, we find lower school enrollment rates and higher participation in special education programs. Our evidence suggests these "extra" conceptions were more likely to face adverse conditions during critical periods of development., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Interpersonal violence in sport occurs in different forms, from emotional abuse, overtraining, bullying, physical aggression and pressuring to punishment and sexual abuse. Due to the use of different definitions, a comparison of prevalence estimates between studies in different countries has not been possible to date. The aim of the current study was thus to present the prevalence estimates of interpersonal violence in elite sport for the Netherlands, Belgium (Flanders), and Germany and to examine the overlap of three types of interpersonal violence. Data from two different surveys (one in the Netherlands and Flanders and another in Germany) of a total of 1,665 elite athletes ( n  = 533 from the Netherlands and Flanders, n  = 1,132 from Germany) were used. Athletes were asked to answer questions about their experiences of psychological, physical, and sexual violence in the context of organized sport. In general, lifetime prevalence estimates for all three types of interpersonal violence are more than 24% in elite athletes, with the highest numbers for psychological violence. Compared to representative population samples the prevalence rate of psychological violence seems to be particularly high. Gender differences were only evident for sexual violence, with female athletes showing higher prevalence estimates than male athletes. Furthermore, a high overlap of experiences of the three different forms of interpersonal violence was found for all three countries. The differences in prevalence estimates between the three countries are discussed.

This paper analyzes Chile's drunk driving laws and their effects on car crashes, injuries, and deaths. There were two policy changes. While the 2012 law increased license suspension penalties and decreased the legal blood alcohol limits for drivers, the 2014 law only increased sanctions, including at least one year of actual imprisonment for drunk driving implicated in car crashes with severe injury or death. We use a rich data set of countrywide administrative records that permit us to identify direct measures of alcohol-related accidents, including fatalities and injuries. We also have access to blood alcohol tests to assess whether the laws affected drivers' alcohol consumption. Using count data models and a rich set of covariates, including police stops and gasoline sales, we find a short-run decrease in accidents and injuries for the 2012 law and a sustained decline in these outcomes for the 2014 law. Neither intervention has an effect on deaths. There is a marginal decline in alcohol consumption after the enactment of both legal changes. However, while the 2012 law only affects male drivers, the 2014 law affects both males and females. No reductions in alcohol intake are found for heavy drinkers.

Do Children and Adolescents with Different Reasons for Admission Equally Benefit from Institutional Care? Currently, almost 150.000 children and adolescents are placed in institutional care in Germany with the aim to improve their living conditions. Various studies showed positive effects concerning the development of those institutionalized children and adolescents. Within the present study, 500 children and adolescents in institutional care were examined regarding the improvement of quality of life and social competencies during their care placement depending on the respective reason for admission (group A: admission due to mental health and behavior problems; group S: problems in the context of the school; group O: no mental health problems, but other reasons). Furthermore, differences in the development of children and adolescents who initiated the placement by themselves and those who did not were examined. Results show that over a period of 18-24 months, all three groups developed effectively equally. Group A had a lower initial level regarding quality of life and social competencies compared to group S and group O and therefore reached lower outcomes within the investigation period. Development was irrespective of whether or not children and adolescents initiated the institutional placement by themselves. The results demonstrate that all three groups were able to benefit from institutional care, although children and adolescents with mental health problems had a notable potential for further development.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177 Lu-DOTA-(d-Glu) 6 -Ala-Tyr-Gly-Trp-Nle-Asp-PheNH 2 ( 177 Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177 Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177 Lu-PP-F11N to assess safety. Results: In all patients, 177 Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different ( P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177 Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177 Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177 Lu-PP-F11N., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Membrane-associated guanylate kinase (MAGUK) with inverted domain structure-1 (MAGI1) is an intracellular adaptor protein that stabilizes epithelial junctions consistent with a tumor suppressive function in several cancers of epithelial origin. Here we report, based on experimental results and human breast cancer (BC) patients' gene expression data, that MAGI1 is highly expressed and acts as tumor suppressor in estrogen receptor (ER) + /HER2 - but not in HER2 + or triple negative breast cancer (TNBC). Within the ER + /HER2 - subset, high MAGI1 expression associates with ESR1 and luminal genes GATA3 and FOXA1 expression and better prognosis, while low MAGI1 levels correlates with higher histological grade, more aggressive phenotype and worse prognosis. Experimentally, MAGI1 downregulation in the ER + human BC cells MCF7 impairs ER expression and signaling, promotes cell proliferation, and reduces apoptosis and epithelial differentiation. MAGI1 downregulation in the ER + murine BC cell line 67NR accelerates primary tumor growth and enhances experimental lung metastasis formation. MAGI1 expression is upregulated by estrogen/ER, downregulated by prostaglandin E2/COX-2axis, and negatively correlates with inflammation in ER + /HER2 - BC patients. Taken together, we show that MAGI1 is a new potential tumor suppressor in ER + /HER2 - breast cancer with possible prognostic value for the identification of patients at high-risk of relapse within this subset., Competing Interests: The authors declare no conflict of interests.

The assessment of Ki-67 in early-stage breast cancer has become an important diagnostic tool in planning adjuvant therapy, particularly for the administration of additional chemotherapy to hormone-responsive patients. An accurate determination of the Ki-67 index is of the utmost importance; however, the reproducibility is currently unsatisfactory. In this study, we addressed the predictive/prognostic value of Ki-67 index assessed by using the most reproducible methods, which were identified in the pilot phase. Paraffin blocks obtained from patients with moderately differentiated, estrogen receptor (ER)-positive early-stage breast cancer in Switzerland, who were originally randomized to the treatment arms with and without chemotherapy in the IBCSG VIII-IX trials, were retrieved. Of these 344 randomized patients, we identified 158 patients (82 treated with and 76 treated without chemotherapy) for whom sufficient tumour tissue was available. The presence of Ki-67 was assessed visually by counting 2000 cells at the periphery (A) and estimating the number of positive cells in five different peripheral regions (C), which was determined to be the most reproducible method identified the pilot phase. The prognostic and predictive value was assessed by calculating the breast cancer-free interval (BCFI) and overall survival (OS) rate. Ki-67 was considered a numerical and categorical variable when different cut-off values were used (10%, 14%, 20% and 30%). An mRNA-based subtyping by using the MammaTyper kit with the application of a 20% Ki-67 immunohistochemistry (IHC) cut-off equivalent was also performed. 158 of 344 randomized patients could be included in the Ki-67 analysis. The mean Ki-67 values obtained by using the two methods differed (A: 21.32% and C: 16.07%). Ki-67 assessed by using method A with a cut-off of 10% was a predictive marker for OS, as the hazard ratio (>10% vs. <=10%) in patients with chemotherapy was 0.48 with a 95% confidence interval of [0.19-1.19]. Further, the HR of patients treated without chemotherapy was 3.72 with a 95% confidence interval of [1.16-11.96] (p interaction =0.007). Higher Ki-67 index was not associated with outcome and using the 10% Ki-67 cut-off there was an opposite association for patients with and without chemotherapy. Ki-67 assessments with IHC significantly correlated with MammaTyper results (p=0.002). The exact counting method (A) performed via a light-microscope revealed the predictive value of Ki-67 assessment with a 10% cut-off value. Further analyses employing image analyses and/or mRNA-based-assessments in larger populations are warranted.

Quality of Life and Behavioral Problems of Unaccompanied Minor Refugees in Child Care Facilities Unaccompanied minor refugees (UMR) who arrive in Germany are generally placed in institutional child care facilities. UMR are a very burdened group, however other children and adolescents in institutional care are burdened as well, and their quality of life is often reduced. The aim of the current study was thus to compare quality of life and behavioral problems of UMR in child care facilities with those of other resident adolescents. For a total of 50 UMR, data regarding behavioral problems was available, for 41 UMR ratings on quality of life, both from external assessments. Two parallel comparison samples of other adolescents in the same institutional care facilities were drawn with adolescents with and without a migration background. Results show that in general, UMR show fewer behavioral problems than the other two groups, especially in externalizing behavior. For internalizing behavior, no differences were evident. For quality of life, no differences could be found between the three groups of inhabitants in institutional care. This indicates that the same factors determining quality of life are present in all three groups, but that the underlying mental problems are different in UMR than in other adolescents. Thus, staff in institutional care should possibly work differently with these group of adolescents than with other inhabitants and should be educated respectively.

Background: To evaluate sensitivity, false negative rate and negative predictive value of the combination of sentinel lymph node (SLN) mapping and frozen section (FS) in triaging cervical cancer patients to a definitive chemo-radiotherapy., Methods: A retrospective analysis of patients with histologically proven cervical cancer undergoing laparoscopic SLN mapping and frozen section of the SLNs followed by a completion radical hysterectomy, pelvic and/or paraarotic lymphadenectomy. Sensitivity, false negative rate and negative predictive value of the SLN mapping, of the frozen section and of the combination of the two in identifying micro- and macrometastases were calculated., Results: One-hundred and four patients with cervical cancer underwent surgery. Of these, 87 (83.7%) had bilateral detection rates at the SLN mapping and underwent FS evaluation and were selected for statistical analysis. Twenty-five patients had lymph nodal metastases at H&E staining. Of these, 24 displayed metastatic disease to the SLNs and one to a NSLN accounting for a FN rate of 4.0%. Metastases were identified in 21 patients at the FS analysis. Four patients had metastases in the SLNs that were missed at the FS analysis. The FN rate of the FS is 12.5% if we excluded isolated tumour cells in the analysis. The FN rate of the combined methodology (SLN mapping and FS of the SLN) is 16%. Twenty-one out of 25 patients (84.0%) could correctly be triaged to a definitive chemo-radiotherapy., Conclusions: The combination of SLN mapping and FS of the SLNs is efficient in triaging patients to a definitive chemo-radiotherapy., (Copyright © 2019. Published by Elsevier Ltd.)

Mental Disorders of Adolescents in Boarding Schools: A Germany-Wide Survey Overall, research on children and adolescents in boarding schools is still scarce. Especially mental disorders of students in boarding schools have not been investigated. As part of this study, a standardized questionnaire survey helped to ask adolescents starting from the age of 15 in boarding schools about mental disorders and depressive symptoms. 169 adolescents from a total of twelve boarding schools in Germany participated in the study. The results of the present Germany-wide survey of adolescents in boarding schools show that the students are a group of rather inconspicuous adolescents, especially the group of boys. Girls show increased risk of depressive behavior and externalizing problems in comparison to the general population. Therefore, child and adolescent psychiatric care should be considered when placed in a boarding school.

Introduction: The evaluation of the trimming surfaces (TS) of tissue blocks from frozen sections may serve as a supplementary examination tool for the intraoperative determination of resection margins of breast cancer specimens. This study aimed at the investigation of the feasibility and reliability of this technique, which has been described only very rarely in literature., Methods: Two observers assessed digital images from TS obtained from 57 resection margins. Findings were correlated with the diagnosis of the frozen section (FS) alone and the final diagnosis on formalin-fixed paraffin-embedded (FFPE) material., Results: The determination of the resection margin on TS was estimated as feasible for all cases. Interobserver congruence rate for TS was 96% (κ = 0.81), which was lower compared with FFPE (100%, κ = 1.0) but superior to FS (89%, κ = 0.67). Intraobserver congruence of the 2 reviewers was 96.5% and 93.0% between TS and FFPE, and 91.1% and 92.5% between FS and FFPE, respectively. The combination of both intraoperative consultation techniques showed similar congruence but a slight improvement for the sensitivity (0.75 to 0.875) for the diagnosis of tumor at the resection margin in FFPE for Reviewer 1 but was unchanged for Reviewer 2., Conclusion: The additional evaluation of TS can be a helpful additional tool for intraoperative margin assessment of breast cancer specimens, in particular, when processing artifacts of FS are encountered.

Introduction: Different approaches have been developed to find the position of the internal auditory canal (IAC) in middle cranial fossa approach. A feasibility study was performed to investigate the combination of cone beam computed tomography (CBCT), optical coherence tomography (OCT), and laser ablation to assist a surgeon in a middle cranial fossa approach by outlining the internal auditory canal (IAC)., Materials and Methods: A combined OCT laser setup was used to outline the position of IAC on the surface of the petrous bone in cadaveric semi-heads. The position of the hidden structures, such as IAC, was determined in MATLAB software using an intraoperative CBCT scan. Four titanium spheres attached to the edge of the craniotomy served as reference markers visible in both CBCT and OCT images in order to transfer the plan to the patient. The integrated erbium-doped yttrium aluminum garnet laser was used to mark the surface of the bone by shallow ablation under OCT-based navigation before the surgeon continued the operation., Result: The technical setup was feasible, and the laser marking of the border of the IAC was performed with an overall accuracy of 300 μm. The depth of each ablation phase was 300 μm. The marks indicating a safe path supported the surgeon in the surgery., Conclusion: The technique investigated in the present study could decrease the surgical risks for the mentioned structures and improve the pace and precision of operation.

The rat lateral fluid-percussion injury (FPI) model has been used extensively to study post-traumatic epilepsy (PTE). Epidemiological studies have reported that the risk of PTE is higher after more severe injury. Adult, male Wistar rats subjected to different atmospheric pressures of injury during FPI showed great variability in injury severity when functional behavior was determined based on the Neurological Severity Score (NSS) assessment. When NSS was used to select rats with the most severe FPI-induced brain injury, 63% of rats experienced at least one convulsive seizure 2-5 weeks after FPI. This same cohort of rats (i.e., selected for severe TBI based on NSS) were significantly more susceptible to PTZ-induced seizures compared to sham controls. Video/EEG recordings from a second cohort of rats with severe FPI-induced injury (based on NSS) showed a similar incidence and frequency of spike wave discharges between rats with severe TBI and sham controls. However, the rate of isolated EEG spikes was greater in rats with severe FPI-induced injury compared to sham controls. These data suggest that convulsive seizures can be obtained in FPI-treated rats when NSS is used as an inclusion criterion to select rats with severe injury. Furthermore, although spike-wave discharges were equally prevalent in rats with severe FPI and sham controls, spontaneous spikes were more prevalent in the rats with severe FPI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Realistic simulations of detailed, biophysics-based, multi-scale models often require very high resolution and, thus, large-scale compute facilities. Existing simulation environments, especially for biomedical applications, are typically designed to allow for high flexibility and generality in model development. Flexibility and model development, however, are often a limiting factor for large-scale simulations. Therefore, new models are typically tested and run on small-scale compute facilities. By using a detailed biophysics-based, chemo-electromechanical skeletal muscle model and the international open-source software library OpenCMISS as an example, we present an approach to upgrade an existing muscle simulation framework from a moderately parallel version toward a massively parallel one that scales both in terms of problem size and in terms of the number of parallel processes. For this purpose, we investigate different modeling, algorithmic and implementational aspects. We present improvements addressing both numerical and parallel scalability. In addition, our approach includes a novel visualization environment which is based on the MegaMol framework and is capable of handling large amounts of simulated data. We present the results of a number of scaling studies at the Tier-1 supercomputer HazelHen at the High Performance Computing Center Stuttgart (HLRS). We improve the overall runtime by a factor of up to 2.6 and achieve good scalability on up to 768 cores.

Adolescents in institutionalized care are at a particularly high risk of exhibiting sexually aggressive behavior including sexual harassment. So far, however, studies about the prevalence of sexually aggressive behavior in institutions are lacking. In this survey, 322 adolescents (43% female, average age 16.7 years) from 32 residential care facilities and boarding schools across Germany were asked about sexually aggressive behavior via a standardized questionnaire. Overall, 23.5% of the participants engaged in some form of sexually aggressive behavior in their lives, and 4.6% reported having committed a sexual assault with (actual or attempted) penetration. A closer look at the circumstances of those offenses shows that the victims were in most cases acquainted with and of the same age as the offenders, that threats and violence were used in some cases, and especially in the case of actual or attempted penetration, and that only a minority of offenders suffered any consequences for their acts. The implementation of protective measures for institutions and the treatment of adolescents in institutions will be discussed.

Objective: The willingness to participate and a sense of security are important aspects to be fostered in the institutional care of adolescents. Although these aspects are increasingly being examined from the perspective of the affected adolescents, it has yet to be considered whether psychological problems can be attributed to their experiences with the above-mentioned aspects., Methods: A total of 216 adolescents aged 14 to 18 years answered an online questionnaire the sense of security in their institution and their perception of the institution. Their willingness to participate was also examined. Psychological symptoms were assessed with the Strengths and Difficulties Questionnaire Self-Report (SDQ-S)., Results: There is a significant correlation between sense of security and the overall SDQ score, with prosocial behavior, and with the positive perception of the institution. In addition, sense of security had a significant influence on the SDQ factors, the positive perception of the institution, and the items on the willingness to participate of the adolescents. The subsequent t-tests also showed significant results. Among other things, it was shown that the factor problems of adolescents is related to sense of security., Conclusion: The results provide an initial indication that there is a link between sense of security and psychological symptoms as well as willingness to participate and perception of the institution. Especially problems of adolescents in dealing with peers must be taken into account.in the development of protective concepts to increase the sense of security and their willingness to participate.

Childhood Experiences of Adolescents in Boarding Schools. A Comparison with Adolescents in Residential Care and with the General Population Various studies indicate that students in boarding schools experience a lot of violence during their accommodation. However, it is not proved whether adolescents in boarding schools are also a burdensome group regarding early childhood experiences such as neglect and abuse. The aim of the study was to find out more about the experiences of adolescents in boarding schools and to determine whether there are differences between adolescents in residential care and between the general population. Furthermore, it should be examined whether boys and girls differ in their experiences. In the study, adolescents of boarding schools and of residential care all over Germany, starting at the age of 15 (n = 322), were asked regarding physical and emotional neglect/abuse, light/severe parent violence, negative/positive educational behavior of the parents. The results show that students in boarding schools were less likely to be affected by childhood maltreatment and more likely to have experienced positive parental behavior compared to children in residential care. Compared to the general population, students in boarding schools were more often and more severely affected by parental violence. Moreover, girls had experienced parental violence more often than boys. The results indicate that in boarding schools there is a need for support offers for adolescents with a history of violent experiences and that the risk group should be identified directly at the admission to the school.

This paper analyzes the effects of lowering the legal blood alcohol content limit for drivers from 0.05 to 0.03 grams of alcohol per deciliter of blood (g/dL) and increasing license suspension periods for offenders. We take advantage of a rich data set of administrative records that allow us to identify direct measures of accidents involving alcohol including fatalities and injuries. Results show a significant decrease of 32% in alcohol-related car accidents right after the law was approved but the effects moderate over time (15% after three years). There is also a significant reduction in injuries (31% right after the approval and 11% after three years) but no statistically significant effects on deaths. Complementary analysis of blood samples shows that the law had an effect on blood alcohol content (BAC) of male drivers up to the 90th percentile of the BAC distribution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An increasingly important issue is the mental strain of professionals in residential care for children and adolescents. However, only few studies investigate mental strain and overload of professionals in an educational context in general and even less in youth welfare institutions. The goal of this study was to examine mental strain experiences of professionals with the "Perceived Stress Questionnaire" (PSQ) in youth welfare institutions, as well as to investigate the relationship between age, duration of employment in this work environment and gender of participants. A total of 426 care providers participated in the online survey. The results tend to show higher stress levels among younger professionals and significantly higher values in tension compared to older employees, but no effect of gender. Furthermore, there is no relation between stress experience and duration of employment in this work environment, but a significant correlation between a feeling of security from violence in this institution and stress level. The total score for stress experience of professionals is similar to that of healthy adults, while in the subscales compared to the norm sample professionals show higher scores on requirements in terms of deadlines and time pressure as well as on tension. The results indicate a high vulnerability of young professionals, which could be addressed by institutional interventions. More studies are needed to clarify causal relationships., Competing Interests: Interessenkonflikt: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

We present a coarse-grained (CG) model of a charged double-stranded DNA immersed in an electrolyte solution that can be used for a variety of electrokinetic applications. The model is based on an earlier rigid and immobile model of Weik et al. and includes now semi-flexibility and mobility, so that DNA dynamics can be sufficiently captured to simulate a full nanopore translocation process. To this end we couple the DNA hydrodynamically via a raspberry approach to a lattice-Boltzmann fluid and parametrize the counterions with a distant dependent friction. The electrokinetic properties of the CG DNA model inside an infinite cylinder is fitted against experimental data from Smeets et al. and all-atom simulation data from Kesselheim et al. The stiffness of our CG DNA is modeled via a harmonic angle potential fitted against experimental data of Brunet et al. Finally, the quality of our tuned parameters is tested by measuring the electrophoretic mobility of our DNA model for various numbers of base pairs and salt concentrations. Our results compare excellently with the experimental data sets of Stellwagen et al. and Hoagland et al.

Research on sexual violence victims and perpetrators indicates that victims in general are found to report higher levels of psychopathological symptoms, especially internalizing behavior, whereas perpetrators often show externalizing behavior. Little is known, however, about the psychopathology of perpetrators of sexual violence who have also experienced sexual victimization (victim-perpetrators). Thus, the aim of the current study was to examine this group within a sample of adolescents living in residential care or federal boarding schools. Participants reported their lifetime experience with sexual violence (both as victim and perpetrator) and completed the Youth Self Report. Results indicate that all three groups of adolescents with sexual violence experience report higher total problem scores than adolescents without this experience. Victim-perpetrators show results more similar to those of perpetrators only than those of victims only. The discussion deals with the implications of our findings for the treatment of victims of sexual violence.

The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.

Competing Interests: There are no conflicts of interest.

The frequency of sexual victimization in high-risk populations like adolescents in institutional care has hardly been studied. In this study, we report lifetime prevalence and incidence from a nationwide German sample including 322 adolescents (mean age 16.69 years, 43% female) from 20 residential care facilities and 12 boarding schools. Lifetime prevalence for severe sexual victimization (in and outside of institution) was 46.7% for girls and 8.0% for boys. Moreover, 5% of all adolescents experienced severe sexual victimization for the first time after they were admitted to the current institution (mean duration of stay in the current institution 3.08 years). Offenders were mostly adolescents of the same age whereas staff members played a minor role as perpetrators. We conclude that the high rate of sexual victimization among adolescents in institutional care should be considered during decision-making processes concerning out-of-home placement and during a stay in residential care., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We report on the case of a 67-year-old man with granulocyte colony-stimulating factor (G-CSF) producing anaplastic carcinoma of the pancreas. Preoperative routine tests revealed an elevated white blood cell (WBC) count of 25.2 G/l, consisting almost exclusively of neutrophilic granulocytes (23.31 G/l) with a predominance of segmented neutrophils (78% of all neutrophilic granulocytes), and elevated levels of C-reactive protein at 87 mg/l. Upon surgery, local tumour infiltration was more extensive than expected from preoperative imaging. However, no peritoneal dissemination was found and curative resection was attempted. Only seven days after the operation, signs of relapse were seen upon computed tomograpy. Histology revealed an undifferentiated anaplastic carcinoma, on the basis of a poorly differentiated ductal adenocarcinoma. Immunohistochemistry demonstrated G-CSF and G-CSF-Receptor expression in some CD68-positive syncytial macrophages. Granulocyte colony-stimulating factor (G-CSF) in serum was elevated at 5.6 pg/ml, which further raised to 43 pg/ml one week after FOLFIRINOX chemotherapy (oxaliplatin, irinotecan, 5-fluorouracil), while WBC decreased from 103.3 G/l to 59.3 G/l. Granulocyte macrophage-colony stimulating factor (GM-CSF) in serum was normal (<0.5 pg/ml). The patient died on postoperative day 34., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation. In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression. This event is accompanied by an increase of intraepithelial lymphocytes, which is an easy to use tool for routine diagnostics using H&E sections. Next generation sequencing (NGS) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene. An individual risk stratification for penetration of these germline mutations is necessary. In conclusion, genetics, phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine.

Disclosure of Adolescents in Residential Care Institutions and Boarding Schools after Exposure to Sexual Violence In international research, many papers exist about the issue of disclosure after having experienced sexual violence. However, specific research regarding disclosure processes of children and adolescents in institutional care are missing, even though those are particularly often affected by sexual violence. In the Germany-wide study "Sprich mit!", adolescents from the age of 15 up (n = 322; average age 16,69 (SD = 1,3); 57,1 % males) who live in residential care or boarding schools were asked for experiences of sexual violence and their consequences by means of a self-report questionnaire. Results showed that the majority of the adolescents (82 %) entrusted themselves to someone, mostly towards peers (56 %) and less frequent towards adults (24 %). Boys and girls opened up equally often, regardless of the severity of the experienced violence. Adolescents who entrusted themselves towards their peers indicated retrospectively more satisfaction than those entrusting themselves towards adults, even if there were no consequences following the disclosure. Considering that the disclosure towards peers did not initiate a process of help, adolescents in institutional care should be better informed about relevant possibilities to entrust themselves and receive support.

Aims: Heart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na(+) /Ca(2+) exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) with HFpEF., Methods and Results: Male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca(2+) transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically., Conclusions: This model of renal HFpEF is associated with slowed relaxation of LV cardiomyocytes. Treatment with SEA0400 improved cardiomyocyte function, remodelling, and HFpEF., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients' informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL™) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.

Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide. Under conditions of abuse, which involve the administration of high repetitive doses, methamphetamine can produce considerable neurotoxic effects. However, recent evidence from our laboratory indicates that low doses of methamphetamine can produce robust neuroprotection when administered within 12h after severe traumatic brain injury (TBI) in rodents. Thus, it appears that methamphetamine under certain circumstances and correct dosing can produce a neuroprotective effect. This review addresses the neuroprotective potential of methamphetamine and focuses on the potential beneficial application for TBI., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.

Background: Walnut consumption is associated with reduced risk of coronary heart disease (CHD)., Objective: We assessed the effect of walnuts on lipid and glucose metabolism, adipokines, inflammation and endothelial function in healthy Caucasian men and postmenopausal women ≥50years old., Design: Forty subjects (mean±SEM: age 60±1years, BMI 24.9±0.6kg/m(2); 30 females) were included in a controlled, cross-over study and randomized to receive first a walnut-enriched (43g/d) and then a Western-type (control) diet or vice-versa, with each lasting 8weeks and separated by a 2-week wash-out. At the beginning and end of each diet phase, measurements of fasting values, a mixed meal test and an assessment of postprandial endothelial function (determination of microcirculation by peripheral artery tonometry) were conducted. Area under the curve (AUC), incremental AUC (iAUC) and treatment×time interaction (shape of the curve) were evaluated for postprandial triglycerides, VLDL-triglycerides, chylomicron-triglycerides, glucose and insulin., Results: Compared with the control diet, the walnut diet significantly reduced non-HDL-cholesterol (walnut vs. control: -10±3 vs. -3±2mg/dL; p=0.025) and apolipoprotein-B (-5.0±1.3 vs. -0.2±1.1mg/dL; p=0.009) after adjusting for age, gender, BMI and diet sequence. Total cholesterol showed a trend toward reduction (p=0.073). Fasting VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and glucose, insulin, HOMA-IR, and HbA1c did not change significantly. Similarly, fasting adipokines, C-reactive protein, biomarkers of endothelial dysfunction, postprandial lipid and glucose metabolism and endothelial function were unaffected., Conclusion: Daily consumption of 43g of walnuts for 8weeks significantly reduced non-HDL-cholesterol and apolipoprotein-B, which may explain in part the epidemiological observation that regular walnut consumption decreases CHD risk., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Neoadjuvant chemoradiotherapy (nCRT) has been established as standard treatment for locally advanced rectal cancer (cT3/4 or cN+ cM0, distance from circumferential resection margin ≤1 mm) to enhance local disease control and minimize the rate of locoregional recurrence. As a consequence of downstaging, a significant proportion of patients show non-viable tumor deposits within regional lymph nodes that qualify as ypN0 according to the current TNM classification irrespective of the actual pre-treatment status. Accordingly, the prognostic relevance of ypN0 status as compared with true pN0 without preceding nCRT is not known., Patients and Methods: We retrospectively analyzed 132 patients who underwent standard total mesorectal excision (TME) surgery after nCRT for rectal carcinoma and were classified as ypN0, and compared their prognoses with those of 341 patients with pN0 without nCRT., Results: Re-evaluation of regional lymph nodes after nCRT showed no evidence of previous metastasis in 91 cases (ypN0(-)), sure but non-viable metastasis in 14 patients (ypN0(+)), and unsure status in 27 patients (ypN0(X)). The local recurrence rate, distant metastases, and disease-free, observed, and cancer-related survival were similar in all subgroups (p = 0.447, 0.695, 0.759, 0.655, and 0.354, respectively)., Conclusion: Our results showed a similar outcome in patients with ypN0 and in the control group with pN0 regarding local recurrence rate, distant metastases, and disease-free, observed, and cancer-related survival. Validation of these results is necessary to clarify the questions regarding postoperative adjuvant chemotherapy for patients with ypN0(+).

Sexual harassment among adolescents has long been neglected in Germany though it is frequent and leads to significant strain for the victims. In international studies, the prevalence of sexual harassment ranges from 10 to 80 % among students. For the development of sexual harassment individual as well as school based factors play a role. Different pathways lead to this problematic behaviour. The effect of new media in the development of sexual harassment cannot be estimated so far. Frequent consequences of sexual harassment in addition to school associated difficulties are unspecific somatic complaints. General practitioners and pediatricians are frequently consulted tn the first place. Recommendations for consultation and interventions are presented., (© Georg Thieme Verlag KG Stuttgart · New York.)

Unlabelled: Integrins are cell surface adhesion molecules (CAM) that regulate via intercellular and cell-matrix signaling various cellular processes including wound healing, cell differentiation, division, growth, migration and metastatic dissemination. Although a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, has been reported, its role in colorectal liver metastases remains unclear. This study aimed to evaluate the expression of β1 integrin in colorectal liver metastases and to correlate the pattern of expression with clinicopathological features and to investigate the putative role of β1 integrin expression on survival of these patients., Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples of 81 patients who were operated because of colorectal liver metastases without any neoadjuvant therapy were obtained and stained with hematoxylin and eosin (H & E). An immunohistochemical examination was performed using Dako, Peroxidase/DAB kit and a primary monoclonal β1 integrin (CD29, fibronectin receptor subunit beta; ab3167, Abcam plc). β1 integrin expression was evaluated according to the immunoreactive score of Remmele and Stegner and was related with clinicopathological features of prognostic significance and with disease-free and overall survival as well. Statistical analysis was performed using SPSS version 21.0., Results: β1 integrin was overexpressed in tumor cells in 37 (48%) patients and in stromal cell in 27 (33%) patients. The β1 expression was not statistically correlated with clinicopathological features of the primary tumors but it was statistically correlated (p=0.03) with the histological grading of liver metastases. Kaplan-Meier survival analysis showed that there is a tendency but no statistically significant correlation in disease-free and overall survival., Conclusion: Considering that expression of β1 integrin in colorectal liver metastases remains controversial, specially its relation with survival of patients, we showed that the β1 expression represents a reliable prognostic factor regarding the grading of liver metastases of CRC and our findings imply that β1 integrin expression profiles may have further potential in identifying the stage of colorectal liver metastases and being a marker of prognosis in these patients.

Purpose: We have previously shown that the addition of cetuximab to chemoradiation therapy failed to improve complete response rates (pCR) in rectal cancer. Here we report the long-term results of the cetuximab added to preoperative radiation therapy with capecitabine and oxaliplatin (CET-CAPOX-RT) phase 1/2 study that evaluated preoperative chemoradiation with cetuximab, capecitabine, and oxaliplatin in patients with rectal cancer., Methods and Materials: The median follow-up was 63 months (range, 5-73 months). Sixty patients were enrolled; 3 patients were excluded due to protocol violation, and 4 died before surgery. Total mesorectal excision was performed in 53 patients, in 85% (n=45) with curative intention (M0-status). Secondary end points including overall survival (OS) disease-free survival (DFS) and cancer-specific survival (CSS) were calculated. The prognostic value of KRAS mutation status was also assessed., Results: Histopathological examination confirmed ypUICC stages 0 (n=4; pCR), I (n=17), II (n=10), III (n=14), and IV (n=8). For patients who underwent surgery (n=53), OS at 1, 3, and 5 years was 88.7%, 83%, and 75.5%, respectively, whereas CSS rates were 94.1%, 88.1%, and 78.1%, respectively. In the 45 patients who were treated with curative intent (M0), the OS rates at 1, 3, and 5 years were 91.1%, 88.9%, and 86.7%, respectively; whereas CSS rates were 97.6%, 95.2%, and 90.3%, respectively; and DFS rates were 90.7%, 88.3%, and 88.3%, respectively. We did not find any locoregional failure in patients with M0-status (n=45). Chronic toxicity was rare. KRAS mutations, as detected in 33.3%, showed no correlation with the clinicopathological parameters nor significance for either OS (P=.112), CSS (P=.264), or DFS (P=.565)., Conclusions: Taken together, chemoradiation therapy combined with cetuximab is safe, feasible, and offers excellent survival rates. KRAS mutation status was not a predictive factor. Importantly, lack of improvement in pCR rate did not translate to poor survival in our clinical trial., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The gastric hormone ghrelin is known as an important factor for energy homeostasis, appetite regulation and control of body weight. So far, ghrelin has mainly been examined as a serological marker for gastrointestinal diseases, and only a few publications have highlighted its role in local effects like mucus secretion. Ghrelin can be regarded as a gastroprotective factor, but little is known about the distribution and activity of ghrelin cells in pathologically modified tissues. We aimed to examine the morphological changes in ghrelin expression under several inflammatory, metaplastic and carcinogenic conditions of the upper gastrointestinal tract. In particular, autoimmune gastritis showed interesting remodeling effects in terms of ghrelin expression within neuroendocrine cell hyperplasia by immunohistochemistry. Using confocal laser microscopy, the gastrin/cholecystokinin receptor (CCKB) could be detected on normal ghrelin cells as well as in autoimmune gastritis. Functionally, we found evidence for a physiological interaction between gastrin and ghrelin in a primary rodent cell culture model. Additionally, we gathered serological data from patients with different basic gastrin levels due to long-term autoimmune gastritis or short-term proton pump inhibitor treatment with slightly reactive plasma gastrin elevations. Total ghrelin plasma levels showed a significantly inverse correlation with gastrin under long-term conditions. Autoimmune gastritis as a relevant condition within gastric carcinogenesis therefore has two effects on ghrelin-positive cells due to hypergastrinemia. On the one hand, gastrin stimulates the proliferation of ghrelinpositive cells as integral part of neuroendocrine cell hyperplasia, while on the other hand, plasma ghrelin is reduced by gastrin and lost in pseudopyloric and intestinal metaplastic areas. Ghrelin is necessary for the maintenance of the mucosal barrier and might play a role in gastric carcinogenesis, if altered under these pre neoplastic conditions.

Although suicidality in medical students is important, few studies dealt with this issue regarding German universities. Our aims were to describe the epidemiology as well as factors leading to suicidality in medical students. Furthermore we wanted to raise awareness for this topic among university employees and show options for handling suicidal crises in students. This manuscript especially aims to address university employees working in direct contact with students (such as student counselors or teachers).

Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.

Background: Self-rated health (SRH) predicts outcome in patients with heart failure. Beta-blockers are known to improve health-related quality of life and reduce mortality in such patients. We aimed to evaluate the relation between SRH and adverse events during titration of beta-blockers in elderly patients with heart failure., Methods: The cardiac insufficiency bisoprolol study in the elderly (CIBIS-ELD) is a multicentre, double-blind trial, in which 883 patients aged ≥ 65 years with chronic heart failure (73 ± 6 years, 38% women, left ventricular ejection fraction [LVEF] 42% ± 14%) were randomised to bisoprolol or carvedilol. SRH was assessed at baseline and after 12 weeks, using a 5-grade descriptive scale: excellent, very good, good, fair, and poor., Results: Median SRH at baseline and follow-up was good, but more patients reported fair/poor SRH at baseline (36% vs. 30%, p = 0.012). Women, beta-blocker-naïve patients, patients in NYHA class III/IV and those with PHQ-9 score ≥ 12 were more likely to report fair/poor baseline SRH (p < 0.001 for all). During follow-up, SRH improved in 34% of patients and worsened in 8% (p < 0.001). Adverse events were experienced by 64% patients and 38% experienced > 1 adverse event or serious adverse event, with higher prevalence in lower SRH categories. In a multivariate logistic regression model, SRH, age, distance achieved on the 6-min walk test and LVEF >45% predicted adverse events (p < 0.05 for all)., Conclusions: SRH is an independent predictor of adverse events during titration of beta-blockers and correlates with the proportion and number of adverse events per patient., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: It has been suggested that patients with chronic HF and atrial fibrillation (AF) may respond differently to beta-blockers than those in sinus rhythm (SR)., Methods: In this predefined analysis of the CIBIS-ELD trial, a total of 876 chronic HF patients (164 patients with AF) were randomized to bisoprolol or carvedilol. During the 12-week-treatment phase, beta-blockers were doubled fortnightly up to the target dose or maximally tolerated dose, which was maintained for 4 weeks., Results: Patients with AF had lower left ventricular ejection fraction (LVEF), exercise capacity, self-rated health, quality of life (QoL) scores for both SF36 physical and psychosocial component, and higher NYHA class than those in SR. Beta-blocker titration was associated with clinical improvement in both AF and SR patients: LVEF, 6-minute walk distance, physical and psychosocial components of QoL scores, self-rated health and NYHA class (p<0.05, for all). The extent of improvement did not differ between patients with AF and in SR and did not differ between bisoprolol and carvedilol. Heart rate (HR) at baseline was higher in the AF group, and remained higher until the end of the trial. Patients with higher baseline HR had larger reductions in HR, regardless of rhythm. AF patients more frequently reached target beta-blocker dose compared to those in SR (p<0.005)., Conclusions: Elderly patients with chronic HF and AF derive comparable clinical benefits from beta-blocker titration as those in SR. Patients with AF tolerate higher beta-blocker doses than those in SR, which appears to be related to higher baseline HR., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The promotion stage in the multistep process of epidermal tumorigenesis is NF-кB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-кB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-кB target genes, p21 and cyclin D1. Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6P+ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-кB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NF-кB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-кB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21 -/- cancer cells and showed that the loss of p21 is cytoprotective against parthenolide. Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6P+ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NF-кB, whereas it increased p21 expression. These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy.

Neonatal brain hypoxia-ischemia (HI) results in neuronal cell death. Previous studies indicate that reactive oxygen species, such as superoxide, play a key role in this process. However, the cellular sources have not been established. In this study we examine the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in neonatal HI brain injury and elucidate its mechanism of activation. Rat hippocampal slices were exposed to oxygen glucose deprivation (OGD) to mimic the conditions seen in HI. Initial studies confirmed an important role for NADPH oxidase-derived superoxide in the oxidative stress associated with OGD. Further, the OGD-mediated increase in apoptotic cell death was inhibited by the NADPH oxidase inhibitor apocynin. The activation of NADPH oxidase was found to be dependent on the p38 mitogen-activated protein kinase-mediated phosphorylation and activation of the p47(phox) subunit. Using an adeno-associated virus antisense construct to selectively decrease p47(phox) expression in neurons showed that this led to inhibition of both the increase in superoxide and the neuronal cell death associated with OGD. We also found that NADPH oxidase inhibition in a neonatal rat model of HI or scavenging hydrogen peroxide reduced brain injury. Thus, we conclude that activation of the NADPH oxidase complex contributes to the oxidative stress during HI and that therapies targeted against this complex could provide neuroprotection against the brain injury associated with neonatal HI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objective: The progesterone receptor (PR) is a ligand-activated transcription factor existing in two isoforms, A (PRA) and B (PRB), resulting from alternative promoter usage. It has long been speculated that genetic variants of PR are associated with the risk for various benign and malignant diseases, but data from clinical trials and in-vitro studies remain contradictory. The most extensively studied variant is termed PROGINS and consists of an intronic 320-bp Alu insertion and two coding (Ser344Thr, Val660Leu) and one silent single nucleotide polymorphism in complete linkage disequilibrium (allele frequency in Caucasians 9-19%). Our study aimed at elucidating the functional consequences of the PROGINS-associated single nucleotide polymorphisms of PRA and PRB (i.e. Thr344 and Leu660) as compared with wild-type PR (Ser344, Val660)., Methods: The two PRA and two PRB full-length receptor variants were expressed by adenovirus in the PR-negative human breast cancer cell line T47D-Y and assayed with respect to transactivational properties, c-src activation, combined net mRNA and protein stability and hormone-binding characteristics., Results: In all experiments the wild-type PR and the PROGINS variant were undistinguishable., Conclusion: Though there still might be tissue specific effects of the variants, our data indicate that these common PR variants do not functionally differ, which may provide a basis to explain the heterogeneous outcome of association studies.