Publications by authors named "Christina Wagner"

46 Publications

Examination of validity, reliability, and interpretability of a self-reported questionnaire on Occupational Balance in Informal Caregivers (OBI-Care) - A Rasch analysis.

PLoS One 2021 23;16(12):e0261815. Epub 2021 Dec 23.

Department of Health Sciences, IMC University of Applied Sciences Krems, Krems, Austria.

Objectives: Informal caregivers often experience a restriction in occupational balance. The self-reported questionnaire on Occupational Balance in Informal Caregivers (OBI-Care) is a measurement instrument to assess occupational balance in informal caregivers. Measurement properties of the German version of the OBI-Care had previously been assessed in parents of preterm infants exclusively. Thus, the aim of this study was to examine the measurement properties of the questionnaire in a mixed population of informal caregivers.

Methods: A psychometric study was conducted, applying a multicenter cross-sectional design. Measurement properties (construct validity, internal consistency, and interpretability) of each subscale of the German version of the OBI-Care were examined. Construct validity was explored by assessing dimensionality, item fit and overall fit to the Rasch model, and threshold ordering. Internal consistency was examined with inter-item correlations, item-total correlations, Cronbach's alpha, and person separation index. Interpretability was assessed by inspecting floor and ceiling effects.

Results: A total of 196 informal caregivers, 171 (87.2%) female and 25 (12.8%) male participated in this study. Mean age of participants was 52.27 (±12.6) years. Subscale 1 was multidimensional, subscale 2 and subscale 3 were unidimensional. All items demonstrated item fit and overall fit to the Rasch model and displayed ordered thresholds. Cronbach's Alpha and person separation index values were excellent for each subscale. There was no evidence of ceiling or floor effects.

Conclusions: We identified satisfying construct validity, internal consistency, and interpretability. Thus, the findings of this study support the application of the German version of the OBI-Care to assess occupational balance in informal caregivers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700023PMC
January 2022

Pembrolizumab plus docetaxel for the treatment of recurrent/metastatic head and neck cancer: A prospective phase I/II study.

Oral Oncol 2022 Jan 26;124:105634. Epub 2021 Nov 26.

Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria.

Background: Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial.

Methods: Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^ plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS).

Results: Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7-11.6) and the median OS 21.3 months (95% CI 6.3-31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia.

Conclusion: DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105634DOI Listing
January 2022

Transfer Function for Relative Blast Overpressure Through Porcine and Human Skulls In Situ.

Mil Med 2021 Oct 22. Epub 2021 Oct 22.

Office of Naval Research, Code 34, Arlington, VA 22203, USA.

Introduction: The overarching objective of the Office of Naval Research sponsored Blast Load Assessment Sense and Test (BLAST) program was to quantify neurofunctional risk from repeated blast exposure. However, human studies have limitations in data collection that can only be addressed by animal models. To utilize a large animal model in this work, researchers developed an approach for scaling blast exposure data from animal to human-equivalent loading. For this study, energy interacting with the brain tissue was selected as a translation metric because of the hypothesized association between observed neurological changes and energy transmitted through the skull. This article describes the methodology used to derive an energy-based transfer function capable of serving as a global correspondence rule for primary blast injury exposure, allowing researchers to derive human-appropriate thresholds from animal data.

Methods And Materials: To generate data for the development of the transfer functions, three disarticulated cadaveric Yucatan minipigs and three postmortem human surrogate heads were exposed to blast overpressure using a large bore, compressed-gas shock tube. Pressure gauges in the free field, on the skull surface, and pressure probes within the brain cavity filled with Sylgard silicone gel recorded the pressure propagation through the skull of each specimen. The frequency components of the freefield and brain cavity measurements from the pig and human surrogates were interrogated in the frequency domain. Doing so quantifies the differences in the amount of energy, in each frequency band, transmitted through both the porcine and the human skull, and the transfer function was calculated to quantify those differences.

Results: Nonlinear energy transmission was observed for both the porcine and human skulls, indicating that linear scaling would not be appropriate for developing porcine to human transfer functions. This study demonstrated similar responses between species with little to no attenuation at frequencies below 30 Hz. The phase of the pressure transmission to the brain is also similar for both species up to approximately 10 kHz. There were two notable differences between the porcine and human surrogates. First, in the 40-100 Hz range, human subjects have approximately 8 dB more pressure transmitted through the skull relative to porcine subjects. Second, in the 1-10 kHz range, human subjects have up to 10 dB more pressure transmitted into the brain (10 dB more attenuation) relative to the porcine subjects.

Conclusions: The fundamental goal of this study was to develop pig-to-human transfer functions to allow researchers to interpret data collected from large animal studies and aid in deriving risk functions for repeated blast exposures. Similarities in porcine and human brain physiology make the minipig experimental model an excellent candidate for blast research. However, differences in the skull geometry have historically made the interpretation of animal data difficult for the purposes of characterizing potential neurological risk in humans. Human equivalent loading conditions are critical so that the thresholds are not over- or underpredicted due to differences in porcine skull geometry. This research provides a solution to this challenge, providing a robust methodology for interpreting animal data for blast research.
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http://dx.doi.org/10.1093/milmed/usab412DOI Listing
October 2021

The Application of Machine Learning to Identify Large Animal Blast Exposure Thresholds.

Mil Med 2021 Oct 22. Epub 2021 Oct 22.

Office of Naval Research, Arlington, VA 22203, USA.

Introduction: The Office of Naval Research sponsored the Blast Load Assessment Sense and Test program to develop a rapid, in-field solution that could be used by team leaders, commanders, and medical personnel to make science-based stand-down decisions for service members exposed to blast overpressure. Toward this goal, the authors propose an ensemble approach based on machine learning (ML) methods to derive a threshold surface for potential neurological deficits that encompasses the intensity of the blast events, the number of exposures, and the period over which the exposures occurred. Because of collection challenges presented by human subjects, the authors utilized data representing a comprehensive set of measures, including structural, behavioral, and cellular changes, from preclinical large animal studies on minipig models. This article describes the development process used to procure the resulting methodology from these studies.

Methods And Materials: Using an ensemble of ML methods applied to experimental data obtained from 71 Yucatan minipigs, the relationship between blast exposure and neurological deficits was delineated. Despite a relatively small sample size, ML methods with k-fold cross-validation (with k = 5) were justified because of the complexity of the dataset reflecting numerous nonlinear relationships between cellular, structural, and behavioral markers. Based on the physiological responses and environmental measures collected during the large animal study, two models were developed to investigate the relationship between multiple outcome measures and exposure to blast. The histological features model was trained on single-exposure animal data to predict a binary injury response (injured or not) using histological features. The environmental features model related the observed behavioral changes to the environmental parameters collected.

Results: The histological features model predicted a binary injury outcome from cellular and physiological measurements. Features identified in developing this classification model showed some level of correlation to observed behavioral changes, suggesting that glial activation inflammation and neurodegenerative responses occur even at the lowest levels of blast exposures tested. The results of the environmental features model, which estimated injury risk from environmental blast exposure characteristics, suggested that the observed changes are not just a function of impulse but an average dynamic impulse rate. Noticeable behavioral deficits were observed at loading rates of 100 kPa (impulse/positive duration) or peak pressures of 300-350 kPa, with an approximate positive phase duration of 3.4 ms for single exposure. Based on this analysis, a 3D threshold surface was developed to characterize the potential risk of neurological deficits.

Conclusions: The ensemble approach facilitated the identification of a pattern of changes across multiple variables to predict the occurrence of changes in brain function. Many changes observed after blast exposure were subtle, making them difficult to measure in human subjects. ML methodologies applied to minipig data demonstrated the value of these techniques in analyzing complex datasets to complement human studies. Importantly, the threshold surface supports the development of science-based blast exposure guidelines.
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http://dx.doi.org/10.1093/milmed/usab410DOI Listing
October 2021

Impact of COVID-19 lockdown on routine oncology versus emergency care at a high volume cancer centre.

Eur J Clin Invest 2021 Aug 4;51(8):e13623. Epub 2021 Jun 4.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: We investigated the influence of population-wide COVID-19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria.

Methods: We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre-lockdown period: 1 January - 15 March 2020) and after (post-lockdown period: 16 March- 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post-lockdown time periods. Patient outcome was described as 3-month mortality rate (3-MM).

Results: In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P < .001). This translates into a 26%-31% reduction of cancer-related patient visits per half month after the lockdown at the ED (P < .001 vs. 2018 + 2019). There was no difference in the distribution of ESI scores at ED presentation (P = .805), admission rates or 3-MM in association with lockdown implementation (P = .086).

Conclusion: We demonstrate the feasibility of maintaining antineoplastic therapy administration during the COVID-19 pandemic. However, our data underline the need for adapted management strategies for emergency presentations of cancer patients.
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http://dx.doi.org/10.1111/eci.13623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209914PMC
August 2021

Evaluation of a Field-Ready Neurofunctional Assessment Tool for Use in a Military Environment.

Mil Med 2021 Apr 30. Epub 2021 Apr 30.

Office of Naval Research, Arlington, VA 22203, USA.

Introduction: The Office of Naval Research sponsored the Blast Load Assessment Sense and Test (BLAST) program to develop a rapid, in-field solution that could be used by team leaders, commanders, and medical personnel to provide a standardized approach to operationally relevant monitoring and analysis of service members exposed to single or repeated low-level blast. A critical piece of the BLAST team's solution was the development of the Brain Gauge technology which includes a cognitive assessment device that measures neurofunctional changes by testing sensory perceptions and a suite of mathematical algorithms that analyze the results of the test. The most recent versions of the technology are easily portable; the device is in the size and shape of a computer mouse. Tests can be administered in a matter of minutes and do not require oversight by a clinician, making Brain Gauge an excellent choice for field use. This paper describes the theoretical underpinnings and performance of a fieldable Brain Gauge technology for use with military populations.

Materials And Methods: The methods used by the Brain Gauge have been documented in over 80 peer-reviewed publications. These papers are reviewed, and the utility of the Brain Gauge is described in terms of those publications.

Results: The Brain Gauge has been demonstrated to be an effective tool for assessing blast-induced neurotrauma and tracking its recovery. Additionally, the method parallels neurophysiological findings of animal models which provide insight into the sensitivity of specific metrics to mechanisms of information processing.

Conclusions: The overall objective of the work was to provide an efficient tool, or tools, that can be effectively used for (1) determining stand-down criteria when critical levels of blast exposure have been reached and (2) tracking the brain health history until return-to-duty status is achieved. Neurofunctional outcome measures will provide the scientific link between blast sensors and the impact of blast on biological health. This calibration process is strengthened with outcome measures that have a biological basis that are paralleled in animal models. The integrative approach that utilizes the Brain Gauge technology will provide a significant advance for assessing the impact of blast exposure and support rapid, science-based decision-making that will ensure mission success and promote the protection of brain health in service members.
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http://dx.doi.org/10.1093/milmed/usab160DOI Listing
April 2021

Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways.

Cell Rep 2021 04;35(1):108956

Zoology, Department of Molecular Physiology, Kiel University, 24118 Kiel, Germany; Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. Electronic address:

Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes.
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http://dx.doi.org/10.1016/j.celrep.2021.108956DOI Listing
April 2021

Sex dependent effect of maternal e-nicotine on F1 Drosophila development and airways.

Sci Rep 2021 02 24;11(1):4441. Epub 2021 Feb 24.

Division of Experimental Asthma Research, Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, German Center for Lung Research (DZL) and the Airway Research Center North (ARCN), Borstel, Germany.

E-cigarettes are heavily advertised as healthier alternative to common tobacco cigarettes, leading more and more women to switch from regular cigarettes to ENDS (electronic nicotine delivery system) during pregnancy. While the noxious consequences of tobacco smoking during pregnancy on the offspring health are well-described, information on the long-term consequences due to maternal use of e-cigarettes do not exist so far. Therefore, we aimed to investigate how maternal e-nicotine influences offspring development from earliest life until adulthood. To this end, virgin female Drosophila melanogaster flies were exposed to nicotine vapor (8 µg nicotine) once per hour for a total of eight times. Following the last exposure, e-nicotine or sham exposed females were mated with non-exposed males. The F1-generation was then analyzed for viability, growth and airway structure. We demonstrate that maternal exposure to e-nicotine not only leads to reduced maternal fertility, but also negatively affects size and weight, as well as tracheal development of the F1-generation, lasting from embryonic stage until adulthood. These results not only underline the need for studies investigating the effects of maternal vaping on offspring health, but also propose our established model for analyzing molecular mechanisms and signaling pathways mediating these intergenerational changes.
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http://dx.doi.org/10.1038/s41598-021-81607-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904947PMC
February 2021

PD-L1 Expression on Tumor Cells Is Associated With a Poor Outcome in a Cohort of Caucasian Nasopharyngeal Carcinoma Patients.

Front Oncol 2019 29;9:1334. Epub 2019 Nov 29.

Department of Internal Medicine I & Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Nasopharyngeal carcinoma (NPC) is endemic in East Asia but rare in the western world. Programmed death ligand 1 (PD-L1) expression on NPC correlates with clinical outcomes. However, data for Caucasian NPC patients are missing. Thus, we performed this retrospective analysis for investigating the potential association of immune checkpoint protein expression with outcome parameters in Caucasian NPC patients. Fifty-five patients with NPC treated between 1993 and 2018 at the Medical University of Vienna were identified. After the exclusion of Asian patients, data on baseline demographic, tumor stage, overall survival (OS), and disease-free survival (DFS) of 30 patients were analyzed. Their tumor samples were stained and scored (low vs. high) for PD-L1, programmed death receptor 1 (PD-1), lymphocyte activating gene 3 (LAG3), and cluster of differentiation 8 (CD8) antibodies. Statistical analysis was performed with Kaplan-Meier plots and log-rank test. Estimated hazard ratios of dichotomized analysis were calculated, together with 95% confidence intervals and -values of Wald tests. PD-L1 expression was ≥50% in 6 (20%) patients, whereas 19 (63%) had ≥1% expression and 5 (17%) tumor samples were PD-L1-negative. While sex and age had no impact on DFS or OS, <50% PD-L1 expression on tumor cells (TC) was associated with a significantly longer OS (log rank test = 0.037; HR 0.275; 95% CI 0.073-1.03). There was no influence on DFS (log rank test = 0.34; HR 0.599; 95% CI 0.208-1.728). However, <10% PD-L1 expression on tumor infiltrating lymphocytes (TILs) was correlated with a worse DFS (log rank test = 0.0057; HR 4.06; 95% CI 1.389-11.868). LAG3 expression or the number of TILs did not play any prognostic role in our population. The PD-L1 expression rate on Caucasians was comparable to that in Asian patients. Although these results have to be interpreted with caution due to the limited number of Caucasian patients available, our data suggest that ≥50% PD-L1 expression on TC is associated with a poor outcome, while ≥10% PD-L1 expression on TILs is correlated with improved DFS. A prospective biomarker analysis of a predefined Caucasian NPC subpopulation would be desirable in future trials.
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http://dx.doi.org/10.3389/fonc.2019.01334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895019PMC
November 2019

Direct Targeting Options for STAT3 and STAT5 in Cancer.

Cancers (Basel) 2019 Dec 3;11(12). Epub 2019 Dec 3.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria.

Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.
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http://dx.doi.org/10.3390/cancers11121930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966570PMC
December 2019

In utero exposure to cigarette smoke and effects across generations: A conference of animals on asthma.

Clin Exp Allergy 2018 11;48(11):1378-1390

Early Life Origins of Chronic Lung Diseases, Research Center Borstel, Leibniz Lung Center, German Center for Lung Research (DZL), Borstel, Germany.

Background: The prevalence of asthma and chronic obstructive pulmonary disease (COPD) has risen markedly over the last decades and is reaching epidemic proportions. However, underlying molecular mechanisms are not fully understood, hampering the urgently needed development of approaches to prevent these diseases. It is well established from epidemiological studies that prenatal exposure to cigarette smoke is one of the main risk factors for aberrant lung function development or reduced fetal growth, but also for the development of asthma and possibly COPD later in life. Of note, recent evidence suggests that the disease risk can be transferred across generations, that is, from grandparents to their grandchildren. While initial studies in mouse models on in utero smoke exposure have provided important mechanistic insights, there are still knowledge gaps that need to be filled.

Objective: Thus, in this review, we summarize current knowledge on this topic derived from mouse models, while also introducing two other relevant animal models: the fruit fly Drosophila melanogaster and the zebrafish Danio rerio.

Methods: This review is based on an intensive review of PubMed-listed transgenerational animal studies from 1902 to 2018 and focuses in detail on selected literature due to space limitations.

Results: This review gives a comprehensive overview of mechanistic insights obtained in studies with the three species, while highlighting the remaining knowledge gaps. We will further discuss potential (dis)advantages of all three animal models.

Conclusion/clinical Relevance: Many studies have already addressed transgenerational inheritance of disease risk in mouse, zebrafish or fly models. We here propose a novel strategy for how these three model organisms can be synergistically combined to achieve a more detailed understanding of in utero cigarette smoke-induced transgenerational inheritance of disease risk.
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http://dx.doi.org/10.1111/cea.13283DOI Listing
November 2018

A model of cigarette smoke induced COPD identifies Nrf2 signaling as an expedient target for intervention.

Aging (Albany NY) 2018 Aug;10(8):2122-2135

Kiel University, Zoology, Department of Molecular Physiology, Kiel, Germany.

Chronic obstructive pulmonary disease (COPD) is among the most important causes of death. Signaling systems that are relevant for tissue repair and detoxification of reactive oxygen species or xenobiotics are thought to be impaired in lungs of patients suffering from this disease. Here, we developed a simple cigarette smoke induced model of COPD based on chronic cigarette smoke exposure that recapitulates major pathological hallmarks of the disease and thus can be used to investigate new therapeutic strategies. Chronic cigarette smoke exposure led to premature death of the animals and induced a set of phenotypes reminiscent of those seen in COPD patients, including reduced physical activity, reduced body fat, increased metabolic rate and a substantial reduction of the respiratory surface. A detailed transcriptomic analysis revealed that especially the TGF-β, Nrf2 and the JAK/STAT signaling pathways are altered by chronic cigarette smoke exposure. Based on these results, we focused on Nrf2 signaling. A pharmacological intervention study performed with oltipraz, an activator of Nrf2 signaling, increased survival of cigarette smoke exposed animals significantly. Thus, the COPD model recapitulates many major hallmarks of COPD and it is highly useful to evaluate the potential of alternative therapeutic strategies.
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http://dx.doi.org/10.18632/aging.101536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128429PMC
August 2018

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal.

Carcinogenesis 2018 04;39(4):534-545

Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna.

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
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http://dx.doi.org/10.1093/carcin/bgy018DOI Listing
April 2018

Nascent RNA signaling to yeast RNA Pol II during transcription elongation.

PLoS One 2018 23;13(3):e0194438. Epub 2018 Mar 23.

Max F. Perutz Laboratories (MFPL); University of Vienna; Vienna, Austria.

Transcription as the key step in gene expression is a highly regulated process. The speed of transcription elongation depends on the underlying gene sequence and varies on a gene by gene basis. The reason for this sequence dependence is not known in detail. Recently, our group studied the cross talk between the nascent RNA and the transcribing RNA polymerase by screening the Escherichia coli genome for RNA sequences with high affinity to RNA Pol by performing genomic SELEX. This approach led to the identification of RNA polymerase-binding APtamers termed "RAPs". RAPs can have positive and negative effects on gene expression. A subgroup is able to downregulate transcription via the activity of the termination factor Rho. In this study, we used a similar SELEX setup using yeast genomic DNA as source of RNA sequences and highly purified yeast RNA Pol II as bait and obtained almost 1300 yeast-derived RAPs. Yeast RAPs are found throughout the genome within genes and antisense to genes, they are overrepresented in the non-transcribed strand of yeast telomeres and underrepresented in intergenic regions. Genes harbouring a RAP are more likely to show lower mRNA levels. By determining the endogenous expression levels as well as using a reporter system, we show that RAPs located within coding regions can reduce the transcript level downstream of the RAP. Here we demonstrate that RAPs represent a novel type of regulatory RNA signal in Saccharomyces cerevisiae that act in cis and interfere with the elongating transcription machinery to reduce the transcriptional output.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194438PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865726PMC
July 2018

Suitability of Secondary PEEK Telescopic Crowns on Zirconia Primary Crowns: The Influence of Fabrication Method and Taper.

Materials (Basel) 2016 Nov 8;9(11). Epub 2016 Nov 8.

Department of Prosthodontics, Dental School, Ludwig-Maximilians-University Munich, Goethestrasse 70, Munich 80336, Germany.

This study investigates the retention load (RL) between ZrO₂ primary crowns and secondary polyetheretherketone (PEEK) crowns made by different fabrication methods with three different tapers. Standardized primary ZrO₂ crowns were fabricated with three different tapers: 0°, 1°, and 2° ( = 10/group). Ten secondary crowns were fabricated (i) milled from breCam BioHPP blanks (PM); (ii) pressed from industrially fabricated PEEK pellets (PP) (BioHPP Pellet); or (iii) pressed from granular PEEK (PG) (BioHPP Granulat). One calibrated operator adjusted all crowns. In total, the RL of 90 secondary crowns were measured in pull-off tests at 50 mm/min, and each specimen was tested 20 times. Two- and one-way ANOVAs followed by a Scheffé's post-hoc test were used for data analysis ( < 0.05). Within crowns with a 0° taper, the PP group showed significantly higher retention load values compared with the other groups. Among the 1° taper, the PM group presented significantly lower retention loads than the PP group. However, the pressing type had no impact on the results. Within the 2° taper, the fabrication method had no influence on the RL. Within the PM group, the 2° taper showed significantly higher retention load compared with the 1° taper. The taper with 0° was in the same range value as the 1° and 2° tapers. No impact of the taper on the retention value was observed between the PP groups. Within the PG groups, the 0° taper presented significantly lower RL than the 1° taper, whereas the 2° taper showed no differences. The fabrication method of the secondary PEEK crowns and taper angles showed no consistent effect within all tested groups.
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http://dx.doi.org/10.3390/ma9110908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457267PMC
November 2016

Airway remodeling in asthma: what really matters.

Cell Tissue Res 2017 03 11;367(3):551-569. Epub 2017 Feb 11.

Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Großhansdorf, Kiel, Lübeck, Germany.

Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.
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http://dx.doi.org/10.1007/s00441-016-2566-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320023PMC
March 2017

Maternal depression research: socioeconomic analysis and density-equalizing mapping of the global research architecture.

Arch Womens Ment Health 2017 02 27;20(1):25-37. Epub 2016 Sep 27.

Department of Social Medicine and Epidemiology, Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt, Germany.

Maternal depression can be accounted for one of the most common complications during pregnancy and the postpartum period affecting women all over the world. So far, no detailed map of the worldwide maternal depression research architecture has been constructed, which encompasses aspects of research activity, quality, and also socioeconomic features. Using the NewQIS platform, density-equalizing mapping projections, scientometric techniques, and economic benchmarking procedures were applied to evaluate global maternal depression research for the period between 1900 and 2012. In total, 7330 related publications and 3335 international collaborations were identified. The USA was the most active country concerning collaborations and total research activity. In the socioeconomic analysis of research activity in high-income countries, Australia was ranked first with an average of 412.05 maternal depression-related publications per 1000 billion US$ GDP (Q), followed by the UK (Q = 373.51) and Canada (Q = 306.32). The group of upper-middle-income countries was led by South Africa (Q = 145.67), followed by Turkey (Q = 91.8). China authored 11.95 maternal depression-related publications per 1000 billion US$ GDP. The USA had the highest activity of maternal depression research per GDP in billion US$ per capita (Q = 60.86). When research activity was related to population size (Q = publications per Mio. inhabitants), Australia (Q = 26.44) was leading the field, followed by Norway (Q = 18.48). Gender analysis revealed a relatively high degree of female scientists involved in this field of research with pronounced differences between single subject areas. In summary, we here present the first picture of the global scientific development in maternal depression research over a period of more than 100 years. The research landscape is clearly dominated by North American and Western European countries, with only minor contribution of Asian or South American countries.
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http://dx.doi.org/10.1007/s00737-016-0669-6DOI Listing
February 2017

Retention force of differently fabricated telescopic PEEK crowns with different tapers.

Dent Mater J 2016 ;35(4):594-600

Department of Prosthodontics, Dental School, Ludwig-Maximilians-University Munich.

To assess the retention force between primary and secondary PEEK crowns made by different fabrication methods. Primary crowns with different tapers (0°, 1°, and 2°) were fabricated and secondary crowns that were either milled from breCam BioHPP blanks, pressed from pellets (BioHPP Pellet) or granules (BioHPP Granulat) were produced. Each specimen was measured 20 times in a pulloff-test and results were analyzed using 2-/1-way ANOVA and linear regression analyses (p<0.05). Within 0° tapered crowns milled secondary crowns showed lower retention forces compared to pressed pellet crowns. Crowns with a 1° taper, however, showed no impact of the fabrication method on retention force. At a 2° taper, granular pressed crowns displayed lower values than their milled counterparts. Within the milled group, a 0° taper showed lower retention values than the higher tapers, whereas in the pressed groups, no impact of taper angle on retention force was found.
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http://dx.doi.org/10.4012/dmj.2015-249DOI Listing
August 2017

Randomized controlled pilot trial of mindfulness-based stress reduction compared to psychoeducational support for persistently fatigued breast and colorectal cancer survivors.

Support Care Cancer 2016 10 17;24(10):4085-96. Epub 2016 May 17.

Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: Cancer-related fatigue (CRF) is a disruptive symptom for many survivors. Despite promising evidence for efficacy of mindfulness-based stress reduction (MBSR) in reducing CRF, no trials comparing it to an active comparator for fatigued survivors have been published. The purpose of this trial was to compare MBSR to psychoeducation for CRF and associated symptoms.

Methods: Breast (n = 60) and colorectal (n = 11) cancer survivors (stage 0-III) with clinically significant CRF after completing chemotherapy and/or radiation therapy an average of 28 months prior to enrollment were randomized to MBSR or psychoeducation/support groups (PES). MBSR focused on mindfulness training; PES focused on CRF self-management. Outcomes included CRF interference (primary), CRF severity and global improvement, vitality, depression, anxiety, sleep disturbance, and pain. Outcomes were assessed at baseline (T1), post-intervention (T2), and 6-month follow-up (T3) using intent-to-treat analysis.

Results: Between-group differences in CRF interference were not significant at any time point; however, there was a trend favoring MBSR (d = -0.46, p = 0.073) at T2. MBSR participants reported significantly greater improvement in vitality (d = 0.53, p = 0.003) and were more likely to report CRF as moderately to completely improved compared to the PES group (χ2 (1) = 4.1765, p = 0.041) at T2. MBSR participants also reported significantly greater reductions in pain at T2 (d = 0.53, p = 0.014). In addition, both MBSR and PES produced moderate-to-large and significant within-group improvements in all fatigue outcomes, depression, anxiety, and sleep at T2 and T3 compared to T1.

Conclusion: MBSR and PES appear efficacious for CRF and related symptoms. Larger trials including a usual care arm are warranted.

Trial Registration: ClinicalTrials.gov Identifier: NCT01724333.
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http://dx.doi.org/10.1007/s00520-016-3220-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221754PMC
October 2016

Retention Load Values of Telescopic Crowns Made of Y-TZP and CoCr with Y-TZP Secondary Crowns: Impact of Different Taper Angles.

Materials (Basel) 2016 May 11;9(5). Epub 2016 May 11.

Department of Prosthodontics, Dental School, Ludwig-Maximilians-University Munich, Goethestrasse 70, Munich 80336, Germany.

This study aimed to examine and compare the retention load values (RL) of different telescopic crown assemblies (Y-TZP and CoCr primary crowns with electroformed and Y-TZP secondary crowns each) with three different taper angles (0°, 1° and 2°). Thirty Y-TZP primary crowns with electroformed gold copings (Z/G group) and Y-TZP secondary crowns (Z/Z group) and 30 CoCr primary crowns with electroformed gold copings (C/G group) and Y-TZP secondary crowns (C/Z group), each with taper angles of 0°, 1° and 2°, were fabricated, respectively. With the exception of the electroformed gold copings, all specimens were Computer-Aided-Design/Computer-Aided-Manufacturing (CAD/CAM)-milled, then sintered and afterwards manually adapted. In order to stabilize the gold copings, they were fixed in a tertiary structure. The secondary crowns were constructed with a hook, which ensured self-alignment with an upper chain. Afterwards, 20 pull-off test cycles were performed in a universal testing machine under artificial saliva and after weighing the secondary crowns with a 5 kg object for 20 s. Data were analyzed by one-way and two-way Analysis of Variance (ANOVA). C/Z with 1° showed higher ( = 0.009) RL than 0° and 2° tapers. C/G at 1° also showed higher ( = 0.001) RL than at tapers of 0° and 2°. Z/G and C/G at 0° showed lower RL than Z/Z and C/Z ( < 0.001). Primary crowns had no impact on the 0° group. Z/G showed lower RL as compared to C/Z within the 1° group ( = 0.007) and Z/Z in the 2° group ( = 0.006). The primary crown material had no influence on RL. Electroformed copings showed lower RL. Further investigations for 1° as well as for the long-term performance after thermomechanical aging are necessary.
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http://dx.doi.org/10.3390/ma9050354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503027PMC
May 2016

Retention Load of Telescopic Crowns with Different Taper Angles between Cobalt-Chromium and Polyetheretherketone Made with Three Different Manufacturing Processes Examined by Pull-Off Test.

J Prosthodont 2018 Feb 1;27(2):162-168. Epub 2016 Apr 1.

Department of Prosthodontics, Dental School, Ludwig-Maximilian-University Munich, Germany.

Purpose: To investigate the retention loads of differently fabricated secondary telescopic polyetheretherketone (PEEK) crowns on cobalt-chromium primary crowns with different tapers.

Materials And Methods: Cobalt-chromium primary crowns with 0°, 1°, and 2° tapers were constructed, milled, and sintered. Corresponding secondary crowns were fabricated by milling, pressing from pellets, and pressing from granules. For these nine test groups, the pull-off tests of each crown combination were performed 20 times, and the retention loads were measured (Zwick 1445, 50 mm/min). Data were analyzed using linear regression, covariance analysis, mixed models, Kruskal-Wallis, and Mann-Whitney U-test, together with the Benferroni-Holm correction.

Results: The mixed models covariance analysis reinforced stable retention load values (p = 0.162) for each single test sequence. There was no interaction between the groups and the separation cycles (p = 0.179). Milled secondary crowns with 0° showed the lowest mean retention load values compared to all tested groups (p = 0.003) followed by those pressed form pellets with 1°. Regarding the different tapers, no effect of manufacturing method on the results was observed within 1° and 2° groups (p = 0.540; p = 0.052); however, among the 0° groups, the milled ones showed significantly the lowest retention load values (p = 0.002). Among the manufacturing methods, both pressed groups showed no impact of taper on the retention load values (p > 0.324 and p > 0.123, respectively), whereas among the milled secondary crowns, the 0° taper showed significantly lower retention load values than the 1° and 2° taper (p < 0.002).

Conclusion: Based on these results, telescopic crowns made of PEEK seem to show stable retention load values for each test sequence; however, data with thermo-mechanical aging are still required. In addition, further developments in CAD/CAM manufacturing of PEEK materials for telescopic crowns are warranted, especially for 0°.
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http://dx.doi.org/10.1111/jopr.12482DOI Listing
February 2018

PEEK Primary Crowns with Cobalt-Chromium, Zirconia and Galvanic Secondary Crowns with Different Tapers-A Comparison of Retention Forces.

Materials (Basel) 2016 Mar 10;9(3). Epub 2016 Mar 10.

Department of Prosthodontics, Dental School, Ludwig-Maximilians-University Munich, Goethestrasse 70, Munich 80336, Germany.

In prosthetic dentistry, double crown systems have proved their suitability as retainers for removable partial dentures. However, investigations in this context, regarding polyetheretherketone, are scarce. Therefore, the aim of this study was to test the retention force (RF) between polyetheretherketone (PEEK) primary and cobalt-chromium (CoCr), zirconia (ZrO₂) and galvanic (GAL) secondary crowns with three different tapers. Primary PEEK-crowns were milled with the tapers 0°, 1°, and 2° (n = 10/taper, respectively). Afterwards, 90 secondary crowns were fabricated: (i) 30 CoCr-crowns milled from Ceramill Sintron (AmannGirrbach, Koblach, Austria) (n = 10/taper), (ii) 30 ZrO₂-crowns milled from Ceramill ZI (AmannGirrbach, Koblach, Austria) (n = 10/taper), and (iii) 30 GAL-crowns made using electroforming (n = 10/taper). RF was measured in a pull-off test (20 pull-offs/specimen) and data were analyzed using 2-/1-way Analysis of Variance (ANOVA) followed by the Tukey-Honestly Significant Difference (HSD) post hoc test and linear regression analyses ( < 0.05). The measured mean RF values ranged between 9.6 and 38.2 N. With regard to the 0°, 1°, and 2° tapered crowns, no statistically significant differences between CoCr and ZrO₂ were observed ( > 0.141). At 0° taper, no differences in retention forces between GAL, CrCr, and ZrO₂ crowns were found ( = 0.075). However, at 1° and 2° taper, lower RF for GAL-crowns were observed ( < 0.009, < 0.001, respectively). According to this laboratory study, PEEK might be a suitable material for primary crowns, regardless of the taper and the material of secondary crown. Long-term results, however, are still necessary.
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http://dx.doi.org/10.3390/ma9030187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456689PMC
March 2016

Poly(inosinic-cytidylic) acid-triggered exacerbation of experimental asthma depends on IL-17A produced by NK cells.

J Immunol 2015 Jun 13;194(12):5615-25. Epub 2015 May 13.

Division of Mouse Models of Asthma, Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, 23845 Borstel, Germany;

Viral infection of the respiratory tract represents the major cause of acute asthma exacerbations. dsRNA is produced as an intermediate during replication of respiratory viruses and triggers immune responses via TLR3. This study aimed at clarifying the mechanisms underlying TLR3 triggered exacerbation of experimental allergic asthma. The TLR3 ligand poly(inosinic-cytidylic) acid was applied intranasally to mice with already established experimental allergic asthma. Airway inflammation, cytokine expression, mucus production, and airway reactivity was assessed in wild-type, IL-17A, or IL-23p19-deficient, and in NK cell-depleted mice. Local application of poly(inosinic-cytidylic) acid exacerbated experimental allergic asthma in mice as characterized by enhanced release of proinflammatory cytokines, aggravated airway inflammation, and increased mucus production together with pronounced airway hyperresponsiveness. This was further associated with augmented production of IL-17 by Th17 cells and NK cells. Whereas experimental exacerbation could be induced in IL-23p19-deficient mice lacking mature, proinflammatory Th17 cells, this was not possible in mice lacking IL-17A or in NK cell-depleted animals. These experiments indicate a central role for IL-17 derived from NK cells but not from Th17 cells in the pathogenesis of virus-triggered exacerbation of experimental asthma.
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http://dx.doi.org/10.4049/jimmunol.1402529DOI Listing
June 2015

Acceptability and Feasibility of a Meaning-Based Intervention for Patients With Advanced Cancer and Their Spouses: A Pilot Study.

Am J Hosp Palliat Care 2016 Jul 9;33(6):546-54. Epub 2015 Mar 9.

Department of Social and Behavioral Sciences, IU Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA

Background: Constructing meaning in cancer leads to improved psychosocial outcomes for patients and survivors.

Aim: We tested the feasibility and preliminary efficacy of a meaning-based intervention for couples.

Design: The single-arm pilot study tested a 4-session, tailored, activities-based couple's intervention.

Setting/participants: Twelve adults with incurable cancer and their partners participated either in a university office or at the couple's home.

Results: The study showed good feasibility. One of the two patients depressed at baseline was no longer depressed at postintervention. Patients' threat appraisals decreased and transcendence increased. In partners, depression, anxiety, and challenge appraisal decreased; threat and secondary appraisals and peace with illness increased.

Conclusions: Our findings suggest feasibility and efficacy, and further research and continued evaluation of this intervention are warranted.
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http://dx.doi.org/10.1177/1049909115575709DOI Listing
July 2016

Illness representations of cancer among healthy residents of Kolkata, India.

Asian Pac J Cancer Prev 2015 ;16(2):845-52

Center for Health Informatics and Policy Weill Cornell Graduate School of Medical Sciences Greenberg Division of Cardiology Weill Cornell Medical College New York, New York, USAE-mail :

Cancer illness representations and screening history among residents of Kolkata, India, were investigated along with socio-demographic characteristics in an effort to understand possible motivations for health behavior. A total of 106 participants were recruited from community locations in Kolkata, India and completed surveys including demographics, the illness perception questionnaire-revised (IPQ-R), and previous experience with cancer and screening practices. Participants were 51.5% college educated, 57% female, 51.5% full-time employed with average age of 32.7 years (R: 18-60 years). Descriptive statistics were generated for the subscales of the IPQ-R, cancer-screening practices and cancer experience. Correlation analyses were conducted to investigate associations between cancer representations and socio-demographic variables. Univariate ANOVAs were calculated to determine gender differences in IPQ-R subscales and differences between participants who knew someone diagnosed with cancer versus those who did not. While 76% of participants knew someone with cancer, only 5% of the sample engaged in cancer screening. Participants perceived cancer as a serious illness with negative emotional valence. Younger age (r(100)=-.36, p<0.001) and male gender (F(1, 98)=5.22, p=0.01, η2=0.05) were associated with better illness coherence. Males also reported greater personal control (F(1, 98)=5.34, p=0.02, η2=0.05) were associated with better illness coherence. Low screening rates precluded analyses of the relationship between illness representations and cancer screening. Cancer was viewed as a threatening and uncontrollable disease among this sample of educated, middle class Kolkata residents. This view may act as a barrier to seeking cancer screening. Public awareness campaigns aimed at improving understanding of the causes, symptoms and consequences of cancer might reduce misunderstandings and fear, especially among women and older populations, who report less comprehension of cancer.
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http://dx.doi.org/10.7314/apjcp.2015.16.2.845DOI Listing
December 2015

Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.

Am J Respir Crit Care Med 2014 Oct;190(7):763-72

1 Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, and.

Rationale: Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined.

Objectives: To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition.

Methods: Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation.

Measurements And Main Results: FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin.

Conclusions: Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.
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http://dx.doi.org/10.1164/rccm.201404-0658OCDOI Listing
October 2014

Development of a 10-year-old full body geometric dataset for computational modeling.

Ann Biomed Eng 2014 Oct 13;42(10):2143-55. Epub 2014 Aug 13.

Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.

The objective of this study was to create a computer-aided design (CAD) geometric dataset of a 10-year-old (10 YO) child. The study includes two phases of efforts. At Phase One, the 10 YO whole body CAD was developed from component computed tomography and magnetic resonance imaging scans of 12 pediatric subjects. Geometrical scaling methods were used to convert all component parts to the average size for a 10 YO child, based on available anthropometric data. Then the component surfaces were compiled and integrated into a complete body. The bony structures and flesh were adjusted as symmetrical to minimize the bias from a single subject while maintaining anthropometrical measurements. Internal organs including the liver, spleen, and kidney were further verified by literature data. At Phase Two, internal characteristics for the cervical spine disc, wrist, hand, pelvis, femur, and tibia were verified with data measured from additional 94 10 YO children. The CAD dataset developed through these processes was mostly within the corridor of one standard deviation (SD) of the mean. In conclusion, a geometric dataset for an average size 10 YO child was created. The dataset serves as a foundation to develop computational 10 YO whole body models for enhanced pediatric injury prevention.
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http://dx.doi.org/10.1007/s10439-014-1078-5DOI Listing
October 2014

Transcriptional regionalization of the fruit fly's airway epithelium.

PLoS One 2014 14;9(7):e102534. Epub 2014 Jul 14.

University of Kiel, Dept. Molecular Physiology, Kiel, Germany; German Center for Lung Research (DZL), Airway Research Center North (ARCN), Germany.

Although airway epithelia are primarily devoted to gas exchange, they have to fulfil a number of different tasks including organ maintenance and the epithelial immune response to fight airborne pathogens. These different tasks are at least partially accomplished by specialized cell types in the epithelium. In addition, a proximal to distal gradient mirroring the transition from airflow conduction to real gas exchange, is also operative. We analysed the airway system of larval Drosophila melanogaster with respect to region-specific expression in the proximal to distal axis. The larval airway system is made of epithelial cells only. We found differential expression between major trunks of the airways and more distal ones comprising primary, secondary and terminal ones. A more detailed analysis was performed using DNA-microarray analysis to identify cohorts of genes that are either predominantly expressed in the dorsal trunks or in the primary/secondary/terminal branches of the airways. Among these differentially expressed genes are especially those involved in signal transduction. Wnt-signalling associated genes for example are predominantly found in secondary/terminal airways. In addition, some G-protein coupled receptors are differentially expressed between both regions of the airways, exemplified by those activated by octopamine or tyramine, the invertebrate counterparts of epinephrine and norepinephrine. Whereas the OAMB is predominantly found in terminal airway regions, the oct3βR has higher expression levels in dorsal trunks. In addition, we observed a significant association of both, genes predominantly expressed in dorsal trunks or in primary to terminal branches branches with those regulated by hypoxia. Taken together, this observed differential expression is indicative for a proximal to distal transcriptional regionalization presumably reflecting functional differences in these parts of the fly's airway system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102534PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097054PMC
January 2016

Depressive rumination and cognitive processes associated with depression in breast cancer patients and their spouses.

Fam Syst Health 2014 Dec 7;32(4):378-88. Epub 2014 Jul 7.

Indiana University School of Medicine.

Depression is common among patients with breast cancer (BC) and their spouses. The diagnosis of BC often results in negative cognitive processes, such as appraisals of harm/loss, intrusive thoughts, and depressive rumination, all of which contribute to the occurrence of depression in both the patient and spouse. The present research is a cross-sectional exploration of the mediating role of depressive rumination in the relationships of intrusive thoughts and appraisal of harm/loss with depression, in a sample of 56 BC patients and their partners. We hypothesized that depressive rumination would mediate the relationships between cognitive processes and depression in both BC patient and their partners. Participants completed self-report measures of depressive symptoms, depressive rumination, cognitive appraisals, and intrusive thoughts. Path analyses using hierarchical linear regression were conducted to assess the relationships among variables. Results indicated that for BC patients, harm/loss appraisals and intrusive thoughts had direct effects on depression; only harm/loss appraisals had indirect effects through depressive rumination. For partners, both harm/loss appraisal and intrusive thoughts had direct effects on depression, and both had indirect effects through depressive rumination. Dyadic analysis showed no relation of partner cognitive variables with patient depression or patient cognitive variables with partner depression. Findings show that the perseverative practice of dwelling on these negative thoughts of loss and harm relates to depressive symptoms. Rumination may act as 1 possible mechanism by which intrusive thoughts and harm/loss appraisals lead to depressive symptoms.
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http://dx.doi.org/10.1037/fsh0000066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260982PMC
December 2014

A Cancer-Indicative microRNA Pattern in Normal Prostate Tissue.

Int J Mol Sci 2013 Mar 4;14(3):5239-49. Epub 2013 Mar 4.

Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.
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http://dx.doi.org/10.3390/ijms14035239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634476PMC
March 2013
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