In vitro studies on the modification of low-dose hyper-radiosensitivity in prostate cancer cells by incubation with genistein and estradiol

<p>Abstract</p> <p>Background</p> <p>As the majority of prostate cancers (PC) express estrogen receptors, we evaluated the combination of radiation and estrogenic stimulation (estrogen and genistein) on the radiosensitivity of PC cells in vitro.</p> <p>Methods</p> <p>PC cells LNCaP (androgen-sensitive) and PC-3 (androgen-independent) were evaluated. Estrogen receptor (ER) expression was analyzed by means of immunostaining. Cells were incubated in FCS-free media with genistein 10 μM and estradiol 10 μM 24 h before irradiation and up to 24 h after irradiation. Clonogenic survival, cell cycle changes, and expression of p21 were assessed.</p> <p>Results</p> <p>LNCaP expressed both ER-α and ER-β, PC-3 did not. Incubation of LNCaP and PC-3 with genistein resulted in a significant reduction of clonogenic survival. Incubation with estradiol exhibited in low concentrations (0.01 μM) stimulatory effects, while higher concentrations did not influence survival. Both genistein 10 μM and estradiol 10 μM increased low-dose hyper-radiosensitivity [HRS] in LNCaP, while hormonal incubation abolished HRS in PC-3. In LNCaP cells hormonal stimulation inhibited p21 induction after irradiation with 4 Gy. In PC-3 cells, the proportion of cells in G2/M was increased after irradiation with 4 Gy.</p> <p>Conclusion</p> <p>We found an increased HRS to low irradiation doses after incubation with estradiol or genistein in ER-α and ER-β positive LNCaP cells. This is of high clinical interest, as this tumor model reflects a locally advanced, androgen dependent PC. In contrast, in ER-α and ER-β negative PC-3 cells we observed an abolishing of the HRS to low irradiation doses by hormonal stimulation. The effects of both tested compounds on survival were ER and p53 independent. Since genistein and estradiol effects in both cell lines were comparable, neither ER- nor p53-expression seemed to play a role in the linked signalling. Nevertheless both compounds targeted the same molecular switch. To identify the underlying molecular mechanisms, further studies are needed.</p

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification

Etablierung einer nationalen Datenbank für die alveoläre Echinokokkose: Detektion von Risikogebieten und Ermittlung der Prävalenz zur Evaluation der Durchseuchungslage in Deutschland

Hintergrund: Die Alveoläre Echinokokkose (AE) ist in Deutschland eine seltene parasitäre Erkrankung durch den Parasiten Echinococcus multilocularis. Viele Fragestellungen zur Epidemiologie, Diagnostik, Behandlung und Versorgung der alveolären Echinokokkose konnten bislang nicht gelöst werden, da die nötigen Strukturen zur Durchführung wissenschaftlicher Arbeiten nicht vorlagen. Ziel war die „Etablierung einer nationalen Datenbank für die alveoläre Echinokokkose“ zur „Detektion von Risikogebieten und Ermittlung der Prävalenz zur Evaluation der Durchseuchungslage“. Material und Methoden: In der Implementierung und Networkingsphase folgte die Kontaktaufnahme mit den beteiligten Akteuren. Dabei erfolgte die Erstellung eines relationalen Datenbankschemas und die Implementierung in MySQL Workbench Version 6.3.5. In der Erhebungs- und Rekrutierungsphase folgte die Kontaktaufnahme, Datenerhebung und Übertragung der Patientendaten in die nationale Datenbank für die alveoläre Echinokokkose. Zur kartographischen Darstellung und Visulisierung der Durchseuchungslage kam die Software EpiInfo™ zum Einsatz. Die Moran’s I-Geoanalyse nach Cluster und Risikogebieten erfolgte mit GeoDa™. Für die statistische Auswertung der N=523 AE-Fälle kam das Auswertungssystem SAS Version 9.2. zum Einsatz. Das Signifikanzniveau wurde bei α=0.05 festgelegt. Ergebnisse: Die Analyse der N=523 AE-Fälle ergab eine Konzentration der Fälle in Baden-Württemberg und Bayern. Die Analyse auf Basis von Moran’s I ergab für Deutschland eine positive räumliche Autokorrelation (I=0.208815 mit Z=32,6175 und einem p-Wert von <0.001). Die Prävalenzschätzung für Deutschland im Zeitraum 1992 - 2016 ergab 0,64 Fälle je 100.000 Einwohner, für Baden-Württemberg lag die geschätzte Prävalenz im gleichen Zeitraum bei 2,18 Fällen je 100.000 Einwohnern und in Bayern wurden in dieser Zeit 1,48 Fälle je 100.000 Einwohner beobachtet. Die Analyse ergab weitere Unterschiede in der Prävalenz von Männern und Frauen. Die Prävalenz bei Frauen beträgt in Deutschland 0,69, für Männer 0,58 Fälle je 100.000 Einwohner in Deutschland. In Baden-Württemberg beträgt die Prävalenz für Frauen 2,33, für die Männer 2,02 Fälle je 100.000 Einwohner. In Bayern 1,31 für Männer, für Frauen 1,65 Fälle je 100.000 Einwohner. Außerdem stieg die alters- und geschlechtsspezifische Prävalenz mit dem Alter an. Die Analyse zur räumlichen Autokorrelation und zu möglichen Risikogebieten zeigt, dass sich die Nachbarschaft von „Hoch-Hoch“-Risikogebieten insbesondere auf die südöstlichen Regionen Baden-Württembergs konzentriert (I=0.188514 mit Z=11,3197 und p<0.001), während das „Hoch-Hoch“-Risikogebiet in Bayern im südwestlichen Teil Bayerns zu finden ist, der in der Nachbarschaft des Baden-Württemberger Risikogebiets liegt bzw. daran angrenzt (I=0.176953 mit Z=13,5144 und p<0.001). Die Risikoanalyse ergab, dass insbesondere die Gemeinden um Leutkirch im Allgäu, Römerstein, Ehingen, Langenau, Herbrechtingen, Münsingen, Moosburg, Bad Waldsee, Vöhringen und Buch sowie Wolfertschwenden und Weitnau „Hoch-Hoch“-Risikogebiete darstellen. Die Prävalenz in Leutkirch im Allgäu beträgt (7 Fälle) 0,31 Fälle je 1.000 Einwohner. Die Prävalenz in Buch (4 Fälle) ergab 1,04 AE-Fälle je 1.000 Einwohner. Die Ortschaft Wolfertschwenden (3 Fälle) weißt eine hohe Prävalenz von 1,58 AE-Erkrankungsfällen je 1.000 Einwohner auf. Diskussion: Die Erfassung von AE-Fällen in die neu etablierte nationale Datenbank für die alveoläre Echinokokkose scheint gut zu funktionieren. Auf Grundlage einer ersten Auswertung der Daten zeigen sich insbesondere die Ortschaften Leutkirch im Allgäu, Römerstein, Ehingen, Langenau, Herbrechtingen, Münsingen, Moosburg, Bad Waldsee, Vöhringen und Buch sowie Wolfertschwenden und Weitnau als präventivpolitisch interessant. Auffallend sind Cluster von Krankheitshäufungen in Bereich der Schwäbischen Alb, der Alpen und dem Alpenvorland. Durch eine Aufklärung der Bevölkerung in „Hoch-Hoch“-Risikogebieten können möglicherweise neue AE-Fälle verhindert bzw. frühzeitig diagnostiziert werden. Eine gezielte Schulung und Ausbildung von Ärztinnen und Ärzten in „Hoch-Hoch“-Risikogebieten zum Erkrankungsbild der alveolären Echinokokkose, ihrer Diagnostik, Behandlung und Versorgung kann möglicherweise dazu beitragen, dass neue Erkrankungsfälle früher diagnostiziert und adäquat behandelt werden können. Fazit: Die neu etablierte nationale Datenbank für die alveoläre Echinokokkose legt im Sinne Rudolf Virchows einen wichtigen Grundstein zur Lösung wichtiger wissenschaftlicher und bislang unbeantworteter Fragstellungen zu dieser seltenen Krankheit

Measurements of the trapezius and erector spinae muscles using virtual touch imaging quantification ultrasound-Elastography: a cross section study

Abstract Background This study uses virtual touch imaging quantification (VTIQ) technology for the first time to conduct measurements of the trapezius and erector spinae muscles in a large study population. The significance of various influencing factors, such as age and sex, are also examined. Method The study population comprised 278 subjects. The Siemens Acuson S3000 and VTIQ technology were used for measurements of the trapezius and erector spinae muscles (Siemens Healthcare, Erlangen, Germany). Results The following mean values ± standard deviation were calculated: left trapezius: males 2.89 ± 0.38 m/s, females 2.71 ± 0.37 m/s; right trapezius: males 2.84 ± 0.41 m/s, females 2.70 ± 0.38 m/s; left erector spinae: males 2.97 ± 0.50 m/s, females 2.81 ± 0.57 m/s; right erector spinae: males 3.00 ± 0.52 m/s, females 2.77 ± 0.59 m/s. A significant difference between male and female subjects was demonstrated both for the shear wave velocities of the trapezius and erector spinae as well as for the thickness of the trapezius muscle (p < 0.05). There was also a significant difference in muscle elasticity between subjects over 60 years of age and those under 60 (p < 0.05). Furthermore, the results indicate that regular physical activity has an effect on muscle elasticity. Conclusions Our results demonstrate significantly different results between male and female subjects and between under- and over-sixty-year-old subjects. This means that sex-related and age-adapted considerations are obviously needed for further studies

Gallbladder polyps – a follow-up study after 11 years

Abstract Background The aim of our study was to investigate the prevalence and natural long-term progression of gallbladder polyps in a random sample of the general population. Methods Four hundred and thirteen subjects (190 women, 223 men; aged 29–75 years) were studied first in 2002 and again eleven years later in 2013. All subjects were interviewed using a standardised questionnaire, anthropometric data were recorded, and an abdominal ultrasound scan was carried out. Results The prevalence of gallbladder polyps was 6.1% (115/1880) in the 2002 study and 12.1% (50/413) in the 2013 follow-up study. After eleven years, 36 subjects (8.7%, 36/413) had developed new polyps, thirteen subjects (48.1%, 13/27) no longer had gallbladder polyps, and 14 subjects (51.9%, 14/27) still had polyps. The number of polyps had increased in six of these subjects (43%, 6/14), decreased in a further six (43%, 6/14), and remained unchanged in two (14%, 2/14). The mean polyp size was 4.7 mm (± 2.2 mm, range 2–20 mm) in 2002 and 4.0 mm (± 1.9 mm, range 0.5–11 mm) at follow-up. A decrease in polyp size was noted in seven (50%) of the 14 subjects, an increase in size in five subjects (35.7%), and no change in two subjects (14.3%). The shape of the polyps had changed from pedunculated to sessile in two subjects (14.3%, 2/14) and from sessile to pedunculated in one subject (7.1%, 1/14). Conclusions In long-term follow-up, the prevalence of gallbladder polyps increased, with new lesions developing in 8.7% of the population. Polyps persisted in 51.9% of the subjects who had them in the original study and disappeared in the other 48.1%

Analysis of vascularization in thyroid gland nodes with superb microvascular imaging (SMI) and CD34 expression histology: a pilot study

Background!#!The Doppler sonography technique known as 'superb microvascular imaging' (SMI) is advancing sonographic micro vascularization imaging in various disciplines. In this study, we aimed to determine whether SMI could reliably reproduce the blood flow in thyroid nodes and whether malignancy could be diagnosed, based on vascularization properties. Immunhistochemical staining by CD34 and SMI where used to determine the vascularization of nodes in terms of quantified vascularization parameters gained by computational evaluation.!##!Methods!#!We used image analysis programs to investigate whether the quantitative value for vascularization strength in the thyroid node, measured with SMI, was correlated with the actual degree of vascularization, determined microscopically. We included 16 patients that underwent thyroid resections. We prepared thyroid gland tissue slices for immunohistochemistry and labelled endothelial cells with CD34 to visualize blood vessels microscopically. We used image analysis programs, ImageJ, to quantify SMI Doppler sonographic measurements and CellProfiler to quantify CD34 expression in histological sections. We evaluated the numeric values for diagnostic value in node differentiation. Furthermore, we compared these values to check for correlations.!##!Results!#!Among the 16 nodes studied, three harboured malignant tumours (18.75%): two papillary and one follicular carcinoma. Among the 13 benign lesions (81.25%), four harboured follicular adenomas. Malignant and benign nodes were not significantly different in sonographic (0.88 ± 0.89 vs. 1.13 ± 0.19; p = 0.2790) or immunohistochemical measurements of vascularization strength (0.05 ± 0.05 vs. 0.08 ± 0.06; p = 0.2260).!##!Conclusion!#!We found a positive, significant correlation (r = 0.55588; p = 0.0254) between SMI (quantitative values for vascularization strength) and immunohistochemistry (CD34 staining) evaluations of thyroid nodes

Elasticity standard values of the Achilles tendon assessed with acoustic radiation force impulse elastography on healthy volunteers: a cross section study

Abstract Background To determine normal values for acoustic radiation force impulse (ARFI) shear wave elastography of the Achilles tendon. Methods Using the VTIQ mode with the Acuson S3000™ (Siemens Healthcare, Erlangen, Germany), we measured the shear wave velocity (SWV) in m/s and the diameter in mm of both Achilles tendons in 182 healthy volunteers. The tendon was displayed in a sagittal view with a relaxed tendon. The parameters were tested for correlations with the anthropometric data of the subjects, between the genders and different age groups, as well as information obtained from the history, such as smoking and sporting activities. Results Using a sagittal acoustic window, we determined a mean SWV of 9.09 ± 0.71 m/s for the left Achilles tendon and 9.17 ± 0.61 m/s for the right. There was a significant difference between the results for the right and left side (p  0.05). The same goes for the consumption of tobacco and alcohol (p > 0.05). Conclusions Age, gender, BMI, smoking or the consumption of alcohol did not affect either the elasticity or the diameter of the Achilles tendon