A new experiment to enable rapid systematic investigations of flux trapping dynamics for superconducting radio-frequency cavity applications.

Many modern accelerators rely on superconducting radio-frequency (SRF) cavities to accelerate particles. When these cavities are cooled to the superconducting state, a fraction of the ambient magnetic field (e.g., Earth's magnetic field) may be trapped in the superconductor. This trapped flux can significantly increase the power dissipation of the SRF cavities. It is, therefore, crucial to understand the underlying mechanism of how magnetic flux is trapped and what treatments and operating conditions can reduce the flux-trapping efficiency. A new experiment was designed that enables a systemic investigation of flux trapping. It allows for independent control of cooldown conditions, which might have an influence on flux trapping: temperature gradient across the superconductor during cooldown, cooldown rate, and ambient magnetic field. For exhaustive studies, the setup was designed for quick thermal cycling, permitting up to 300 superconducting transitions in one day. In this paper, the setup and operation is described in detail and an estimation of the measurement errors is given. Exemplary data are presented to illustrate the efficacy of the system.

Retrospective study on the pharyngeal airspace in the lateral cephalogram - A mathematical model to predict changes due to bimaxillary orthognathic surgery.

The aim of this study was the development of a statistical model for reliable prediction of Posterior Airway Space (PAS) changes in lateral cephalograms (LCR) of patients after bimaxillary orthognathic surgery. The LCRs of patients who underwent bimaxillary orthognathic surgery were retrospectively analyzed. The anteroposterior dimension of the PAS was measured at three levels in the pre-operative and postoperative LCR: On the nasopharyngeal (SPAS), oropharyngeal (MAS), and hypopharyngeal level (IAS). The data of 139 patients were collected. The following changes of the PAS were measured: in class II patients SPAS: 0.291 mm (SD = 2.570 mm); MAS: 2.444 mm (SD = 2.986 mm); IAS: 0.750 mm (SD = 3.017 mm); in class III patients SPAS: 1.377 mm (SD 3.212 mm); MAS: 0.962 (SD: = 3.135 mm); IAS: 0.370 mm (SD = 3.468 mm). Linear regression analysis showed for class II patients, a significant influence of mandibular movement on MAS (p = 0.049) and a significant effect of maxillary and mandibular movements on SPAS (p = 0.001) and MAS (p = 0.022) in class III patients. The other jaw displacements had no significant impact on the investigated PAS levels. While the presented method does not permit exact prediction of the dimension of the PAS, it is still an easily accessible method of orientation for the surgeon. The surgeon can initiate three-dimensional examinations to provide exact three-dimensional prediction based on this calculation.

Short- and long-term outcome in cats diagnosed with pyothorax: 47 cases (2009-2018).

OBJECTIVES: The aims of this retrospective study were to report the short- and long-term outcome in cats treated for pyothorax and to identify prognostic indicators as well as determine recurrence rate. METHODS: Medical records from April 2009 to August 2018 were retrospectively reviewed. Cases were included if a diagnosis of pyothorax was confirmed via cytology and/or culture of pleural fluid. Cats diagnosed with or suspected of having other thoracic diseases and cats with no evidence of pleural effusion were excluded from the study. RESULTS: Fifty-five cats met the inclusion criteria. Eighty five percent (n=47) cats underwent medical management with thoracostomy tubes, pleural lavage and broad-spectrum antibiotics. Fifteen percent (n=5) cases failed medical treatment and underwent thoracotomy. Twenty eight percent (n=13) did not survive to hospital discharge. Short-term survival (14 days) was achieved in 72% (n=34). Long-term follow-up was available for 31 of 34 with a long-term survival rate of 68% (n=30). The recurrence rate was 6% (n=2). CONCLUSION: For cats with pyothorax that survive to discharge the prognosis is excellent and the condition is associated with a low recurrence rate.

A novel serum-free medium for the isolation, expansion and maintenance of stemness and tissue-specific markers of primary human periodontal ligament cells.

PURPOSE: Periodontal ligament (PDL) cell cultures are classically maintained in serum-containing media. However, unwanted side-effects of these conditions on cellular and molecular characteristics demand a serum-free alternative. Even though these limitations are well known and efforts for the development of adequate serum-free alternatives have been made, these approaches for replacement remained unsuccessful so far. This study aimed at developing a well-defined, serum-free formulation supporting both isolation from tissue samples and efficient expansion of PDL cells. Here, of particular focus was the perpetuation of tissue-characteristic markers detectable in primary tissues and of stemness features. BASIC PROCEDURES: Primary PDL cell cultures from generally healthy human donors (n = 3) were maintained in basal media N2B27 and E6 together with different concentrations of growth and attachment factors. Cell proliferation was recorded via microscopy and WST assay. Gene expression of RUNX2, Periostin, ALP, CD73, CD90, CD105, CD45, SOX10 and SOX2 was compared to primary PDL explants via qRT-PCR. Immunocytochemistry was performed for anti-CD105, SSEA-3, CD271, HNK1. Serum-containing sDMEM medium served as control. MAIN FINDINGS: N2B27 medium substituted with 25 ng/mL EGF, 25 ng/mL IGF1, 0.5 mg/mL Fetuin plus gelatine coating (designated N2B27-PDLsf) emerged as potent serum-free formulation ensuring adequate culture isolation and expansion. Here, PDL primary tissue signature markers RUNX2 and Periostin remained stable in N2B27-PDLsf compared to controls (229.0-fold ±101.0 and 83.2-fold ±9.6 increase). Additionally, stemness markers ALP and CD105 were significantly upregulated on transcriptional, and CD105 and SOX2 on protein level. PRINCIPAL CONCLUSIONS: This investigation identified a novel serum-free medium for the isolation, and expansion of primary human PDL cells with constantly high proliferation rates. Here, purity and stemness properties are maintained. Thus, N2B27-PDLsf represents a valid replacement for serum-containing media in PDL cultures.

The beneficial effect of cold atmospheric plasma on parameters of molecules and cell function involved in wound healing in human osteoblast-like cells in vitro.

The aim of this study was to analyse the effect of cold atmospheric plasma (CAP) on human osteoblast-like cells in vitro. Additionally, underlying intracellular mechanisms were to be studied. Human osteoblast-like (MG63) cells were exposed to CAP for 60 s. The effects of CAP on key molecules essential for the wound healing response were studied using real-time PCR, ELISA and immunocytochemistry. For studying intracellular signalling pathways, MAP kinase MEK 1/2 was blocked. Cell viability was analysed by an XTT assay and with an EVE automated cell counter. Cell migration was examined by an in vitro wound healing assay.CAP exposition on osteoblast-like cells caused a significant upregulation of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)α, cyclooxygenase (COX)2, collagen (COL) 1α, matrix metalloproteinase (MMP)1, Ki67, proliferating-cell-nuclear-antigen (PCNA) and chemokine ligand (CCL)2 mRNA expression at 1 day. Interestingly, after blocking of MAP kinase, CAP-induced upregulation of Ki67 was inhibited by 57%. Moreover, CAP treatment improved significantly osteoblast-like cell viability as compared to untreated cells at 1 day. Beneficial effect of CAP treatment was shown by an in vitro wound healing assay, displaying a significant faster wound closure. Our findings provide evidence that CAP exposure effects gene and protein regulation in human osteoblast-like cells. Furthermore, CAP treatment has a positive impact on wound closure in an in vitro setting and might improve existing concepts of hard tissue regeneration in the future.

Determination of scotopic and photopic conventional visual acuity and hyperacuity.

PURPOSE: Visual acuity (VA) is an important determinant of visual function. Here we establish procedures and recommendations for VA testing extending beyond the classical VA and thus make them available for future studies of visual function in health and disease. Specifically, we provide reference values for photopic and scotopic conventional uncrowded visual acuity (cVA) and Vernier-hyperacuity (hVA) and assess their reproducibility and dependence on contrast polarity. METHODS: For ten observers with normal vision, we determined photopic ("p"; maximal luminance 220 cd/m2) and scotopic ("s"; maximal luminance 0.004 cd/m2; 40 min of dark adaptation) cVA and hVA, for two contrast polarities i.e. black optotypes on white background and vice versa. To assess intersession effects, two sets of measurements were obtained on different days. RESULTS: Compared to pcVA (1.32 decimal VA; - 0.12 ± 0.02 LogMAR), the phVA (14.45 decimal VA; - 1.16 ± 0.04 LogMAR) scaled (in terms of decimal visual acuity) on average with a factor 11.0, the scVA (0.12 decimal VA; 0.91 ± 0.03 LogMAR) with a factor of 0.1, and the shVA (1.47 decimal VA; - 0.17 ± 0.02 LogMAR) with a factor of 1.1. There were neither significant effects of contrast polarity (p > 0.12), nor of session (p > 0.28). CONCLUSIONS: Our approach optimises integrated photopic and scotopic cVA and hVA measurements for general use and thus encourages the integration of these important measures of scotopic visual function in future studies. The absence of strong intersession effects demonstrates that no dedicated training session is needed to obtain scotopic and hVA measurements. The combined measures of scotopic and photopic VAs open a field of applications to study interplay and plasticity of the retinal photoreceptor systems and cortical processing in health and visual disease. As a rule of thumb, hyperacuity is 10× higher both in the photopic and scotopic range than conventional acuity. Thus, scotopic hyperacuity is close to photopic conventional acuity.

Scotopic multifocal visual evoked potentials.

OBJECTIVE: To investigate the scope of scotopic multifocal visual evoked potentials (mfVEPS) for the assessment of scotopic visual fields. METHODS: Pattern-reversal mfVEP for photopic (mfVEPP) and scotopic conditions (mfVEPS; 0.003 cd/m2) were recorded from 36 visual field locations of a circular checkerboard pattern (25° radius) in 9 participants with normal vision. MfVEPP were recorded with a conventional central fixation cross, mfVEPS were recorded (i) with (mfVEPS+) and (ii) without (mfVEPS-) an additional fixation aid. Latency shifts were determined using cross-correlations, mfVEP magnitudes were analysed in an eccentricity dependent manner using signal-to-noise ratios (SNRs). RESULTS: In comparison to mfVEPP, mfVEPS- and mfVEPS+ were delayed by 101 ms and 97 ms, respectively, and had smaller signal-to-noise-ratios. Both mfVEPS were reduced down to noise level in the center and also severely reduced for the most peripheral stimulus eccentricity used. The visual-field-coverage for the paracentral eccentricities of mfVEPS+ and mfVEPS- was 76% and 65% [4°-9°], respectively, and 79% and 66% [9°-16°]. CONCLUSIONS: MfVEPS were delayed compared to mfVEPP and demonstrated the expected central response drop-out typical for scotopic vision. SIGNIFICANCE: MfVEPS may hold promise of an objective, spatially resolved visual field test which motivates testing it in patients with diseases affecting scotopic vision.

Cognitive Performance Does not Limit Physical Activity Participation in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVES: We examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity (PA) adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). DESIGN, SETTING, PARTICIPANTS: The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a PA intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults. INTERVENTION: A 12-month structured, moderate-intensity, multi-modal PA program that included walking, resistance training, and flexibility exercises. For the first 2 months (adoption), 3 center-based exercise sessions (40-60 min) / week were conducted. During the next 4 months (transition), center-based sessions were conducted 2 times / week. The subsequent maintenance phase consisted of optional once-to-twice-per-week center-based sessions and home-based PA. MEASUREMENTS: Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. RESULTS: 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the PA arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar PA adherence rates (all P ≥ 0.34). Furthermore, weak and non-significant univariate relationships were elicited between all measures of cognition and overall PA adherence levels (r values ranged: -0.20 to 0.12, P ≥ 0.12). CONCLUSION: These data suggest that cognitive performance does not limit long-term PA adherence in mobility-limited older adults. Additional studies in larger cohorts are warranted to verify these findings.

Influence of TGF-ß1 on tumor transition in oral cancer cell and BMSC co-cultures.

OBJECTIVES: TGF-ß1 signaling modulates epithelial mesenchymal transitions (EMT) of head and neck squamous cell carcinoma (HNSCC). Bone marrow mesenchymal stromal cells (BMSC) are able to exert a regulating influence on the expression of markers of EMT in HNSCC cells. It was thus the aim of this study to test the hypothesis that TGF-ß1 modulates the interactions of tumor transition between BMSCs and HNSCC, affecting the expression of E-cadherin, Vimentin, Snail, Twist, MMP14 and beta-catenin. Furthermore, we analyzed alterations in the AKT-signaling of tumor and stroma cells. MATERIALS AND METHODS: BMSCs were isolated from iliac bone marrow aspirates and co-cultured in trans-well permeable membrane wells with tumor cells of the established HNSCC cell line PCI-13. Following the induction with TGF-ß1 under serum free conditions the expression of Vimentin and E-Cadherin was assessed via immunofluorescence. A quantitative RT-PCR analysis of tumor transition markers E-cadherin, Vimentin, Snail, Twist, MMP14 and beta-catenin was performed. Changes in AKT-Signaling were identified via protein analysis. RESULTS: In non-induced co-cultures, BMSC were able to suppress Vimentin in PCI-13 as a marker of tumor transition. In TGF-ß1 induced co-cultures PCI-13 significantly increased the expression of Vimentin, Twist, Snail, MMP14, GSK3a, PRAS40, 4E-BP1, and AMPKa compared to monolayer controls. TGF-ß1 co-cultured BMSC demonstrated a significant increase of Snail, PRAS40, mTOR, GSK3a/b, Bad, PDK1 and 4E-BP1. CONCLUSIONS: TGF-ß1 was able to attenuate the modulating influence of BMSC in co-culture and drive the co-culture towards a progressive tumor transition, affecting the expression of markers of EMT, AKT-Signaling and proliferative checkpoints.

Daily changes of individual gait patterns identified by means of support vector machines.

Despite the common knowledge about the individual character of human gait patterns and about their non-repeatability, little is known about their stability, their interactions and their changes over time. Variations of gait patterns are typically described as random deviations around a stable mean curve derived from groups, which appear due to noise or experimental insufficiencies. The purpose of this study is to examine the nature of intrinsic inter-session variability in more detail by proving separable characteristics of gait patterns between individuals as well as within individuals in repeated measurement sessions. Eight healthy subjects performed 15 gait trials at a self-selected speed on eight days within two weeks. For each trial, the time-continuous ground reaction forces and lower body kinematics were quantified. A total of 960 gait patterns were analysed by means of support vector machines and the coefficient of multiple correlation. The results emphasise the remarkable amount of individual characteristics in human gait. Support vector machines results showed an error-free assignment of gait patterns to the corresponding individual. Thus, differences in gait patterns between individuals seem to be persistent over two weeks. Within the range of individual gait patterns, day specific characteristics could be distinguished by classification rates of 97.3% and 59.5% for the eight-day classification of lower body joint angles and ground reaction forces, respectively. Hence, gait patterns can be assumed not to be constant over time and rather exhibit discernible daily changes within previously stated good repeatability. Advantages for more individual and situational diagnoses or therapy are identified.

A flexible setup for angle-resolved X-ray fluorescence spectrometry with laboratory sources.

X-ray fluorescence (XRF) analysis is one of the standard tools for the analysis of stratified materials and is widely applied for the investigation of electronics and coatings. The composition and thickness of the layers can be determined quantitatively and non-destructively. Recent work showed that these capabilities can be extended towards retrieving stratigraphic information like concentration depth profiles using angle-resolved XRF (ARXRF). This paper introduces an experimental sample chamber which was developed as a multi-purpose tool enabling different measurement geometries suited for transmission measurements, conventional XRF, ARXRF, etc. The chamber was specifically designed for attaching all kinds of laboratory X-ray sources for the soft and hard X-ray ranges as well as various detection systems. In detail, a setup for ARXRF using an X-ray tube with a polycapillary X-ray lens as source is presented. For such a type of setup, both the spectral and lateral characterizations of the radiation field are crucial for quantitative ARXRF measurements. The characterization is validated with the help of a stratified validation sample.

Can piezoelectric ultrasound osteotomies result in serious noise trauma?

The use of ultrasound to cut bone in oral and craniofacial surgery has increased. There is concern that the application of ultrasound to the craniofacial skeleton might represent a potential hazard to the inner ear because of sound transmission by bone conduction resulting in hearing trauma. Conventional and ultrasound osteotomies were performed on human specimens of temporal bone containing an intact middle and inner ear. The equivalent sound pressure was measured with a microphone at the round window, which had been calibrated with a bone conduction audiometer. Conventional osteotomy with a rose burr resulted in maximum sound pressures of 125dB(A) consisting of major frequency components at 2100, 7600, and 9300Hz. Ultrasound osteotomy resulted in maximum sound pressures of 122dB(A) and exhibited major frequency components at around 10kHz, 20kHz, and 26.5kHz. Ultrasound osteotomies have no acoustic advantage over conventional osteotomies. Both osteotomy techniques can produce noise-induced hearing trauma, especially when applied over longer durations of time. This appears to be more relevant for ultrasound osteotomies, because the bone cutting efficiency is usually poorer than in conventional osteotomies. Surgeons should consider the risk of noise-induced potential damage to the inner ear when selecting the method of osteotomy.

Interactions of human MSC with head and neck squamous cell carcinoma cell line PCI-13 reduce markers of epithelia-mesenchymal transition.

OBJECTIVES: Cancer progression is influenced by tumor microenvironment and communication of stromal cells and tumor cells. Interactions may enhance epithelial-mesenchymal transition (EMT) of tumor cells through signaling proteins such as Wnt/beta-catenin and matrix metalloproteinases (MMP), as well as loss of cellular integrity, which affects invasion, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC). In this study, we are testing the hypothesis that interactions of human mesenchymal stromal cells (MSCs) with HNSCC might influence the expression of markers of EMT and tumor progression by co-culturing human MSC with the PCI-13 HNSCC line. MATERIALS AND METHODS: Pooled MSCs were derived from the iliac bone marrow of seven patients and co-cultured in transwell permeable membrane wells with tumor cells of the established HNSCC cell line PCI-13 (UICC: T3, N1, M0). MSCs were characterized through fluorescence-activated cell sorting (FACS) analysis. Expression of Wnt3, E-cadherin, beta-catenin, MMP14, cathepsin b, and ETS1 was assessed by quantitative RT-PCR. RESULTS: We were able to show that co-culture of MSCs and PCI-13 leads to a significantly reduced expression of Wnt3, MMP14, and beta-catenin compared to controls, whereas the expression of cathepsin b and ETS1 was not significantly different between co-cultures and controls. CONCLUSION: Our results suggest that the interaction between MSCs and PCI-13 may suppress EMT in cancer cells. CLINICAL RELEVANCE: The influence of MSCs can suppress the onset of EMT in HNSCC, affecting tumor progression and therapy.

UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to the heat shock protein 90 inhibitor ganetespib.

HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC50s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50>500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment.

Use of the Sentinel Lymph Node Technique Compared to Complete Inguino-femoral Lymph Node Removal in Patients with Invasive Vulvar Cancer in Germany.

In the current S2 guidelines, the standard surgical therapy for patients with vulvar cancer also includes inguino-femoral lymphadenectomy. However, in view of the severe side-effects associated with this approach such as problems with wound healing, lymphoceles and lymphoedema, the search is on for alternative treatments that could decrease treatment-associated morbidity and improve patients' quality of life, particularly for node-negative patients. The sentinel lymph node technique is currently the gold standard in the treatment of unifocal breast cancer (clinically negative axilla), and studies on the use of this technique in the treatment of vulvar cancer are promising. To date, the diagnostic accuracy of this method in vulvar cancer has only been evaluated in a single, one-arm, non-randomised, multicentre study. In preparation for a multicentre study, in 2010 we surveyed 41 German hospitals to investigate how often they used the sentinel lymph node technique compared to inguino-femoral lymphadenectomy. The hospitals were grouped according to hospital size and number of patients treated for vulvar cancer. The decision criteria to determine the type of procedure performed were also investigated. Finally, the hospitals were asked whether they would be willing to participate in a prospective clinical study to evaluate the sentinel lymph node technique in patients with vulvar cancer. The majority of surgeons questioned (73 %) already had some experience with this technique in patients with vulvar cancer. In our survey, 27 % of hospitals carried out inguino-femoral lymphadenectomy, 10 % used the sentinel lymph node technique, and 63 % used both methods. In 24 % of hospitals, the standard procedure consisted of the sentinel lymph node technique supplemented by inguino-femoral lymphadenectomy. Only 20 % of the institutions surveyed in our study carried out sentinel lymph node biopsy alone in accordance with the criteria of the consensus recommendations. The majority of the investigated institutions were willing to participate in a randomised prospective clinical study to evaluate the effectiveness of sentinel lymph node sampling in patients with vulvar cancer.

Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear ß-catenin in cerebral metastasis of lung adenocarcinomas.

An essential function of the transcription factors LEF1/TCF4 in cerebral metastases of lung adenocarcinomas has been described in mouse models, suggesting a WNT/ß-catenin effect as potential mechanism. Their role in humans is still unclear, thus we analyzed LEF1, TCF4, ß-catenin, and early stage prognostic markers in 25 adenocarcinoma brain metastases using immunohistochemistry (IHC). IHC revealed nuclear TCF4 in all adenocarcinoma samples, whereas only 36 % depicted nuclear LEF1 and nuclear ß-catenin signals. Samples with nuclear LEF1 as well as high TCF4 (++++) expression were associated with a shorter survival (p = 0.01, HR = 6.68), while nuclear ß-catenin had no significant impact on prognosis and did not significantly correlate with nuclear LEF1. High proliferation index Ki67 was associated with shorter survival in late-stage disease (p = 0.03, HR 3.27). Additionally, we generated a LEF1/TCF4 as well as an AXIN2 signature, the latter as representative of WNT/ß-catenin activity, following a bioinformatics approach with a gene expression dataset of cerebral metastases in lung adenocarcinoma. To analyze the prognostic relevance in primary lung adenocarcinomas, we applied both signatures to a microarray dataset of 58 primary lung adenocarcinomas. Only the LEF1/TCF4 signature was able to separate clusters with impact on survival (p = 0.01, HR = 0.32). These clusters displayed diverging enrichment patterns of the cell cycle pathway. In conclusion, our data show that LEF1/TCF4, but not ß-catenin, have prognostic relevance in primary and cerebrally metastasized human lung adenocarcinomas. In contrast to the previous in vivo findings, these results indicate that LEF1/TCF4 act independently of ß-catenin in this setting.

Lipid and other plasma markers are associated with anxiety, depression, and fatigue.

OBJECTIVE: Few peripheral metabolites have been shown to be associated with mood in healthy individuals or patients with central nervous system diseases. During military basic combat training (BCT), mood state, physical performance and body composition substantially improve, providing an opportunity to examine relationships between mood and nutritional and hormonal biomarkers. METHOD: Thirty-five females enrolled in U.S. Marine BCT, an intense physically and mentally challenging 12-week course, were studied. Every 4 weeks, mood was assessed with the Profile of Mood States (POMS), as were nutritional, metabolic and hormonal plasma markers. RESULTS: Mood and fitness improved over BCT, and there were substantial changes in biochemical markers. Multiple regression demonstrated that, in combination, cholesterol (HDL, LDL), fructosamine, triglycerides, free fatty acids (FFA), dehydroepiandrosterone-sulfate (DHEA-S), ACTH, and substance P accounted for 44% of variation in anxiety, 40% confusion, 37% fatigue, 27% depression and 40% in total mood (p < .0001). Increased HDL, FFA, DHEA-S, and substance P were associated with degraded mood (p < .05). Increased LDL, triglycerides, fructosamine, and ACTH were associated with improved mood (p < .05). Other markers, including glucose, cortisol, and C-reactive protein were not associated with mood. CONCLUSIONS: Normal human mood state was associated with 8 plasma markers. Increased HDL and lower LDL, which are associated with improved cardiovascular status, were associated with negative affect. Fructosamine and substance P, not previously known to be related to mood, were associated with it. We are not aware of any biological parameters that in aggregate predict such a substantial proportion of variation in normal mood.

[Climate change - a pioneer for the expansion of canine vector-borne diseases?]. / Der Klimawandel - Wegbereiter für die Ausbreitung vektorübertragener Erkrankungen des Hundes?

Vector-transmitted diseases are one of the major contributors to the global burden of disease in humans and animals. Climate change is consistently held responsible for the spread of parasitic acarid and insect vectors such as ticks, fleas, sand flies and mosquitoes, and their transmitted pathogens (in the case of the dog the so-called canine vector-borne diseases [CVBD]). Currently, there is only insufficient data available to prove whether climate change is a major driving force for vector and disease expansion, but the evidence is growing. Other reasons, such as ecological, demographic and socio-economic factors, e.g. pet travel into and pet import from endemic areas, also play a role in this development. Apart from all the controversial discussion of the factors leading to vector and disease expansion, preventative measures should include dog owners' education as they are responsible for individual parasite protection as well as for the minimisation of adverse risk behaviour, e.g. regarding pet travel. Broad-spectrum vector control should be practised by using parasiticides that repel and kill blood feeders in order to minimize the risk of CVBD-pathogen transmission.

Appetite and endocrine regulators of energy balance after 2 days of energy restriction: insulin, leptin, ghrelin, and DHEA-S.

Using a double-blind, placebo-controlled crossover design, the effects of 48 h near complete energy restriction on endocrine regulators of appetite and satiety were assessed. Twelve men and one woman participated in this controlled, 2-day diet intervention study. One experimental trial was completed in a calorie deprived state (CAL-DEP; <10% of estimated energy requirements) and others in a fed condition (carbohydrate only and carbohydrate and fat; data were pooled and compared to CAL-DEP). Test meals containing prescribed energy intake and indistinguishable in sensory characteristics were provided during each trial. Glucose, insulin, leptin, ghrelin, cortisol, dehydroepiandrosterone-sulfate (DHEA-S), and satiety were repeatedly assessed. Mean glucose, insulin, and leptin concentrations were lower (P < 0.0001) for CAL-DEP compared to the fully fed (FED) state. Ghrelin and DHEA-S were higher (P < 0.0001) for CAL-DEP relative to FED. Cortisol levels declined each day regardless of diet (P < 0.0001) but were 32% higher (P < 0.01) at the conclusion of the session for CAL-DEP compared to FED. Satiety was 25% lower (P < 0.0001) for CAL-DEP relative to FED and decreased (P < 0.0001) over time regardless of diet. In the FED state, insulin (r = 0.55), glucose (r = 0.76), cortisol (r = -0.59), and DHEA-S (r = -0.62) were associated (P < 0.05) with satiety, but not during CAL-DEP. These findings show that 2 days of severe energy restriction alter several endocrine regulators of appetite independent of perception of increased hunger suggesting a physiological mechanism to explain overeating following acute periods of severe energy restriction.

ß-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of ß-catenin remained uninfluenced. Consistently, ß-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. ß-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.