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Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt(s_NN)=130 GeV using the STAR TPC at RHIC. The elliptic flow signal, v_2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Background: Evaluation of automated attenuation-based tube potential selection and its impact on image quality and radiation dose in CT (computed tomography) examinations for cancer staging.
Methods: A total of 110 (59 men, 51 women) patients underwent chest-abdomen-pelvis CT examinations; 55 using a fixed tube potential of 120 kV/current of 210 Reference mAs (using CareDose4D), and 55 using automated attenuation-based tube potential selection (CAREkV) also using a current of 210 Reference mAs. This evaluation was performed as a single-centre, observer-blinded retrospective analysis. Image quality was assessed by two readers in consensus. Attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured or calculated for objective image evaluation. For the evaluation of radiation exposure, dose-length-product (DLP) values were compared and Size-specific dose estimates (SSDE) values were calculated.
Results: Diagnostic image quality was obtained from all patients. The median DLP (703.5 mGy · cm, range 390–2203 mGy · cm) was 7.9% lower when using the algorithm compared with the standard 120 kV protocol (median 756 mGy · cm, range 345–2267 mGy · cm). A reduction in potential to 100 kV occurred in 32 cases; therefore, these patients received significantly lower radiation exposure compared with the 120 kV protocol.
Conclusion: Automated attenuation-based tube potential selection produces good diagnostic image quality in chest-abdomen-pelvis CT and reduces the patient’s overall radiation dose by 7.9% compared to the standard 120 kV protocol.
Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition.
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.
Mechanisms by which specific histone modifications regulate distinct gene regulatory networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression in mammalian cardiogenesis. Early embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific gene regulatory networks at two critical cardiogenic junctures: left ventricle patterning and postnatal cardiomyocyte cell cycle withdrawal. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, these analyses also revealed that H3K79me2 in specific regulatory elements contributed to silencing genes usually not expressed in cardiomyocytes. As DOT1L mutants had increased numbers of postnatal mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity, controlled inhibition of DOT1L might be a strategy to promote cardiac regeneration post-injury.
Background: In Germany, about 20% of the total population have a migration background. Differences exist between migrants and non-migrants in terms of health care access and utilisation. Colorectal cancer is the second most common malignant tumour in Germany, and incidence, staging and survival chances depend, amongst other things, on ethnicity and lifestyle. The current study investigates whether stage at diagnosis differs between migrants and non-migrants with colorectal cancer in an area of high migration and attempts to identify factors that can explain any differences.
Methods/Design: Data on tumour and migration status will be collected for 1,200 consecutive patients that have received a new, histologically verified diagnosis of colorectal cancer in a high migration area in Germany in the previous three months. The recruitment process is expected to take 16 months and will include gastroenterological private practices and certified centres for intestinal diseases. Descriptive and analytical analysis will be performed: the distribution of variables for migrants versus non-migrants and participants versus non-participants will be analysed using appropriate χ2-, t-, F- or Wilcoxon tests. Multivariable, logistic regression models will be performed, with the dependent variable being the dichotomized stage of the tumour (UICC stage I versus more advanced than UICC stage I). Odds ratios and associated 95%-confidence intervals will be calculated. Furthermore, ordered logistic regression models will be estimated, with the exact stage of the tumour at diagnosis as the dependent variable. Predictors used in the ordered logistic regression will be patient characteristics that are specific to migrants as well as patient characteristics that are not. Interaction models will be estimated in order to investigate whether the effects of patient characteristics on stage of tumour at the time of the initial diagnosis is different in migrants, compared to non-migrants.
Discussion: An association of migration status or other socioeconomic variables with stage at diagnosis of colorectal cancer would be an important finding with respect to equal health care access among migrants. It would point to access barriers or different symptom appraisal and, in the long term, could contribute to the development of new health care concepts for migrants.
Trial registration: German Clinical Trials Register DRKS00005056.
Most sRNA biogenesis mechanisms involve either RNAseIII cleavage or ping-pong amplification by different Piwi proteins harboring slicer activity. Here, we follow the question why the mechanism of transgene-induced silencing in the ciliate Paramecium needs both Dicer activity and two Ptiwi proteins. This pathway involves primary siRNAs produced from non-translatable transgenes and secondary siRNAs from endogenous remote loci. Our data does not indicate any signatures from ping-pong amplification but Dicer cleavage of long dsRNA. We show that Ptiwi13 and 14 have different preferences for primary and secondary siRNAs but do not load them mutually exclusive. Both Piwis enrich for antisense RNAs and Ptiwi14 loaded siRNAs show a 5′-U signature. Both Ptiwis show in addition a general preference for Uridine-rich sRNAs along the entire sRNA length. Our data indicates both Ptiwis and 2’-O-methylation to contribute to strand selection of Dicer cleaved siRNAs. This unexpected function of two distinct vegetative Piwis extends the increasing knowledge of the diversity of Piwi functions in diverse silencing pathways. As both Ptiwis show differential subcellular localisation, Ptiwi13 in the cytoplasm and Ptiwi14 in the vegetative macronucleus, we conclude that cytosolic and nuclear silencing factors are necessary for efficient chromatin silencing.
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Sprach- und Sprechstörungen kommen bei zahlreichen Kindern vor und werden in der ICD-11 analog zur ICD-10 als Entwicklungsstörungen im Kapitel 6 (Psychische, Verhaltens- und Entwicklungsstörungen) klassifiziert. International sind bislang die ICD-10-Kriterien nicht von allen Professionen, die sich mit Sprach- und Sprechstörungen klinisch oder im Rahmen der Forschung beschäftigen, akzeptiert. Sie werden einerseits als zu wenig differenziert hinsichtlich der unterschiedlichen Sprachkomponenten vonseiten der Linguistik, Sprachtherapie oder Logopädie erlebt. Zum anderen wird die unklare Abgrenzung organisch bedingter Sprach- und Sprechprobleme von der Sprachentwicklungsstörung vonseiten der Medizin teilweise kritisch bewertet. In dem vorliegenden Artikel wird deshalb einerseits die Klassifikation von Sprach- und Sprechproblemen und -störungen in der ICD-11 im Vergleich zur ICD-10 vorgenommen. Wesentlich erscheint hier die in der ICD-11 neu eingeführte Differenzierung in „primäre“ und „sekundäre“ Neuroentwicklungsstörungen. Zum anderen erfolgt aber auch eine Auseinandersetzung mit dem DSM-5 sowie anderen Klassifikationsvorschlägen vonseiten der englischsprachigen Sprachtherapie (CATALISE-2) und der deutschsprachigen Pädaudiologie („phonologische Wahrnehmungsstörung“) sowie der Vorschlag einer Ergänzung der aktuellen ICD-11-Klassifikation hinsichtlich konkreter sprachlicher Einschränkungen bei einem Kind mit Sprachentwicklungsstörung, basierend auf einer ausführlichen Diagnostik. Wir hoffen, mit dem Artikel so den Weg für eine berufsübergreifende Klassifikation von Sprach- und Sprechstörungen nach ICD-11 zu bahnen, damit perspektivisch alle Berufsgruppen, die Diagnostik und Therapie der betroffenen Personen anbieten, eine vergleichbare Terminologie verwenden. Diese vergleichbare Terminologie soll sowohl die klinische Versorgung verbessern als auch die unterschiedlichen Forschungsansätze und -richtungen vergleichbarer machen.