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Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.
Background/aims: Hepatocellular carcinoma (HCC) is a leading indication for liver transplantation (LT) worldwide. Early identification of patients at risk for HCC recurrence is of paramount importance since early treatment of recurrent HCC after LT may be associated with increased survival. We evaluated incidence of and predictors for HCC recurrence, with a focus on the course of AFP levels.
Methods: We performed a retrospective, single-center study of 99 HCC patients who underwent LT between January 28th, 1997 and May 11th, 2016. A multi-stage proportional hazards model with three stages was used to evaluate potential predictive markers, both by univariate and multivariable analysis, for influences on 1) recurrence after transplantation, 2) mortality without HCC recurrence, and 3) mortality after recurrence.
Results: 19/99 HCC patients showed recurrence after LT. Waiting time was not associated with overall HCC recurrence (HR = 1, p = 0.979). Similarly, waiting time did not affect mortality in LT recipients both with (HR = 0.97, p = 0.282) or without (HR = 0.99, p = 0.685) HCC recurrence. Log10-transformed AFP values at the time of LT (HR 1.75, p = 0.023) as well as after LT (HR 2.07, p = 0.037) were significantly associated with recurrence. Median survival in patients with a ratio (AFP at recurrence divided by AFP 3 months before recurrence) of 0.5 was greater than 70 months, as compared to a median of only 8 months in patients with a ratio of 5.
Conclusion: A rise in AFP levels rather than an absolute threshold could help to identify patients at short-term risk for HCC recurrence post LT, which may allow intensification of the surveillance strategy on an individualized basis.
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
Anti-angiogenesis in hepatocellular carcinoma treatment : current evidence and future perspectives
(2011)
Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as “bridging” therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospecretrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.
Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
Abstract: The hallmarks of Alzheimer’s disease (AD) are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP) has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ) highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs) was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI) networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.
Author Summary: More than 20 years ago, the amyloid precursor protein (APP) was identified as the precursor protein of the Aβ peptide, the main component of senile plaques in brains affected by Alzheimer’s disease. However, little is known about the physiological function of amyloid precursor protein. Allocating APP to the proteome of the structurally and functionally dynamic presynaptic active zone highlights APP as a hitherto unknown player within the presynaptic network. The hippocampus is the most prominent brain region for learning and memory consolidation, and a vulnerable target for neurodegenerative disease, e. g. Alzheimer’s disease. Therefore, our experimental design is focused on the hippocampal neurotransmitter release site. Currently, the underlying mechanism of how APP acts within presynaptic networks is still elusive. Within the scope of this research article, we constructed a network of APP within the presynaptic active zone and how deletion of APP affects these individual networks. We combine bioinformatics tools and biochemical approaches to address the dataset provided by proteomics. Furthermore, we could unravel that APP executes regulatory functions within the synaptic vesicle cycle, cytoskeletal rearrangements and Ca2+-homeostasis. Taken together, our findings offer a new perspective on the physiological function of APP in the central nervous system and may provide a molecular link to the pathogenesis of Alzheimer’s disease.
The amyloid precursor protein (APP) was discovered in the 1980s as the precursor protein of the amyloid A4 peptide. The amyloid A4 peptide, also known as A-beta (Aβ), is the main constituent of senile plaques implicated in Alzheimer’s disease (AD). In association with the amyloid deposits, increasing impairments in learning and memory as well as the degeneration of neurons especially in the hippocampus formation are hallmarks of the pathogenesis of AD. Within the last decades much effort has been expended into understanding the pathogenesis of AD. However, little is known about the physiological role of APP within the central nervous system (CNS). Allocating APP to the proteome of the highly dynamic presynaptic active zone (PAZ) identified APP as a novel player within this neuronal communication and signaling network. The analysis of the hippocampal PAZ proteome derived from APP-mutant mice demonstrates that APP is tightly embedded in the underlying protein network. Strikingly, APP deletion accounts for major dysregulation within the PAZ proteome network. Ca2+-homeostasis, neurotransmitter release and mitochondrial function are affected and resemble the outcome during the pathogenesis of AD. The observed changes in protein abundance that occur in the absence of APP as well as in AD suggest that APP is a structural and functional regulator within the hippocampal PAZ proteome. Within this review article, we intend to introduce APP as an important player within the hippocampal PAZ proteome and to outline the impact of APP deletion on individual PAZ proteome subcommunities.
Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.
Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).
Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).
Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
The ALICE collaboration at the LHC reports measurement of the inclusive production cross section of electrons from semi-leptonic decays of beauty hadrons with rapidity |y|<0.8 and transverse momentum 1<pT<10 GeV/c, in pp collisions at s√= 2.76 TeV. Electrons not originating from semi-electronic decay of beauty hadrons are suppressed using the impact parameter of the corresponding tracks. The production cross section of beauty decay electrons is compared to the result obtained with an alternative method which uses the distribution of the azimuthal angle between heavy-flavour decay electrons and charged hadrons. Perturbative QCD calculations agree with the measured cross section within the experimental and theoretical uncertainties. The integrated visible cross section, σb→e=3.47±0.40(stat)+1.12−1.33(sys)±0.07(norm)μb, was extrapolated to full phase space using Fixed Order plus Next-to-Leading Log (FONLL) predictions to obtain the total bb¯ production cross section, σbb¯=130±15.1(stat)+42.1−49.8(sys)+3.4−3.1(extr)±2.5(norm)±4.4(BR)μb.
The ALICE collaboration at the LHC reports measurement of the inclusive production cross section of electrons from semi-leptonic decays of beauty hadrons with rapidity |y|<0.8 and transverse momentum 1<pT<10 GeV/c, in pp collisions at s√= 2.76 TeV. Electrons not originating from semi-electronic decay of beauty hadrons are suppressed using the impact parameter of the corresponding tracks. The production cross section of beauty decay electrons is compared to the result obtained with an alternative method which uses the distribution of the azimuthal angle between heavy-flavour decay electrons and charged hadrons. Perturbative QCD calculations agree with the measured cross section within the experimental and theoretical uncertainties. The integrated visible cross section, σb→e=3.47±0.40(stat)+1.12−1.33(sys)±0.07(norm)μb, was extrapolated to full phase space using Fixed Order plus Next-to-Leading Log (FONLL) predictions to obtain the total bb¯ production cross section, σbb¯=130±15.1(stat)+42.1−49.8(sys)+3.4−3.1(extr)±2.5(norm)±4.4(BR)μb.
The differential charged jet cross sections, jet fragmentation distributions, and jet shapes are measured in minimum bias proton-proton collisions at centre-of-mass energy s√=7 TeV using the ALICE detector at the LHC. Jets are reconstructed from charged particle momenta in the mid-rapidity region using the sequential recombination kT and anti-kT as well as the SISCone jet finding algorithms with several resolution parameters in the range R=0.2 to 0.6. Differential jet production cross sections measured with the three jet finders are in agreement in the transverse momentum (pT) interval 20<pjet,chT<100 GeV/c. They are also consistent with prior measurements carried out at the LHC by the ATLAS collaboration. The jet charged particle multiplicity rises monotonically with increasing jet pT, in qualitative agreement with prior observations at lower energies. The transverse profiles of leading jets are investigated using radial momentum density distributions as well as distributions of the average radius containing 80% (⟨R80⟩) of the reconstructed jet pT. The fragmentation of leading jets with R=0.4 using scaled pT spectra of the jet constituents is studied. The measurements are compared to model calculations from event generators (PYTHIA, PHOJET, HERWIG). The measured radial density distributions and ⟨R80⟩ distributions are well described by the PYTHIA model (tune Perugia-2011). The fragmentation distributions are better described by HERWIG.
The differential charged jet cross sections, jet fragmentation distributions, and jet shapes are measured in minimum bias proton-proton collisions at centre-of-mass energy s√=7 TeV using the ALICE detector at the LHC. Jets are reconstructed from charged particle momenta in the mid-rapidity region using the sequential recombination kT and anti-kT as well as the SISCone jet finding algorithms with several resolution parameters in the range R=0.2 to 0.6. Differential jet production cross sections measured with the three jet finders are in agreement in the transverse momentum (pT) interval 20<pjet,chT<100 GeV/c. They are also consistent with prior measurements carried out at the LHC by the ATLAS collaboration. The jet charged particle multiplicity rises monotonically with increasing jet pT, in qualitative agreement with prior observations at lower energies. The transverse profiles of leading jets are investigated using radial momentum density distributions as well as distributions of the average radius containing 80% (⟨R80⟩) of the reconstructed jet pT. The fragmentation of leading jets with R=0.4 using scaled pT spectra of the jet constituents is studied. The measurements are compared to model calculations from event generators (PYTHIA, PHOJET, HERWIG). The measured radial density distributions and ⟨R80⟩ distributions are well described by the PYTHIA model (tune Perugia-2011). The fragmentation distributions are better described by HERWIG.
The differential charged jet cross sections, jet fragmentation distributions, and jet shapes are measured in minimum bias proton-proton collisions at centre-of-mass energy s√=7 TeV using the ALICE detector at the LHC. Jets are reconstructed from charged particle momenta in the mid-rapidity region using the sequential recombination kT and anti-kT as well as the SISCone jet finding algorithms with several resolution parameters in the range R=0.2 to 0.6. Differential jet production cross sections measured with the three jet finders are in agreement in the transverse momentum (pT) interval 20<pjet,chT<100 GeV/c. They are also consistent with prior measurements carried out at the LHC by the ATLAS collaboration. The jet charged particle multiplicity rises monotonically with increasing jet pT, in qualitative agreement with prior observations at lower energies. The transverse profiles of leading jets are investigated using radial momentum density distributions as well as distributions of the average radius containing 80% (⟨R80⟩) of the reconstructed jet pT. The fragmentation of leading jets with R=0.4 using scaled pT spectra of the jet constituents is studied. The measurements are compared to model calculations from event generators (PYTHIA, PHOJET, HERWIG). The measured radial density distributions and ⟨R80⟩ distributions are well described by the PYTHIA model (tune Perugia-2011). The fragmentation distributions are better described by HERWIG.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced.
(2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored.
(3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%.
(4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Objectives: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail.
Methods: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list.
Results: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0–1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died.
Conclusions: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients.
Comparative proteomics reveals a diagnostic signature for pulmonary head‐and‐neck cancer metastasis
(2018)
Patients with head‐and‐neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head‐and‐neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross‐ and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.
Objectives: Stenosis of the biliary anastomosis predisposes liver graft recipients to bacterial cholangitis. Antibiotic therapy (AT) is performed according to individual clinical judgment, but duration of AT remains unclear.
Methods: All liver graft recipients with acute cholangitis according to the Tokyo criteria grade 1 and 2 after endoscopic retrograde cholangiography (ERC) were included. Outcome of patients treated with short AT (<7 days) was compared to long AT (>6 days). Recurrent cholangitis (RC) within 28 days was the primary end point.
Results: In total, 30 patients were included with a median of 313 (range 34–9849) days after liver transplantation until first proven cholangitis. Among 62 cases in total, 51/62 (82%) were graded as Tokyo-1 and 11/62 (18%) as Tokyo-2. Overall median duration of AT was 6 days (1–14) with 36 cases (58%) receiving short AT and 26 (42%) receiving long AT. RC was observed in 10 (16%) cases, without significant difference in occurrence of RC in short versus long AT cases. CRP and bilirubin were significantly higher in patients with long AT, while low serum albumin and low platelets were associated with risk of RC.
Conclusion: A shorter antibiotic course than 7 days shows good results in selected, ERC-treated patients for post-transplantation biliary strictures.
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.
Determination of field strength and quality factor of heavily HOM damped accelerator cavities
(1992)
Two methods of of measuring field strength in accelerator cavities, heavily damped with respect to higher order modes (HOM), are presented. From the results of the field measurements the coupling (damping) factor and thus the quality factor of the damped resonator can be derived. Measurements of a pillbox resonator with heavily damped TM110-mode (Q < 20) demonstrate the usefulness of the techniques presented, even in this extreme range.
Poster presentation: Background Maraviroc is a new drug used to treat HIV infection from the new class of drugs called CCR5 entry inhibitors. As the active principle of these drugs is to block the CCR5-receptor on the surface of the target cells, it has to be known if the virus in the patient is using only CCR5 as co-receptor or if there are populations that can also use CXCR4. Therefore, an assay to determine the tropism has to be performed before starting a therapy. Besides phenotypic assays like the TROFILE® assay by Monogram, used in the approval studies, there exist several genotyping systems like geno2pheno-coreceptor, Wetcat (providing five different genotypic tropism schemes) and WebPSSM. ...
Different collective deformation coordinates for neutrons and protons are introduced to allow for both stretching and γ transitions consistent with experiments. The rotational actinide nuclei 234-238U and 232Th are successfully analyzed in this model. NUCLEAR STRUCTURE 232Th, 234-238U calculated B (E2) values, collective model.
Objectives: Investigate the effectiveness of a complex intervention aimed at improving the appropriateness of medication in older patients with multimorbidity in general practice.
Design: Pragmatic, cluster randomised controlled trial with general practice as unit of randomisation.
Setting: 72 general practices in Hesse, Germany.
Participants: 505 randomly sampled, cognitively intact patients (≥60 years, ≥3 chronic conditions under pharmacological treatment, ≥5 long-term drug prescriptions with systemic effects); 465 patients and 71 practices completed the study.
Interventions: Intervention group (IG): The healthcare assistant conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision support system, the general practitioner optimised medication, discussed it with patients and adjusted it accordingly. The control group (CG) continued with usual care.
Outcome measures: The primary outcome was a modified Medication Appropriateness Index (MAI, excluding item 10 on cost-effectiveness), assessed in blinded medication reviews and calculated as the difference between baseline and after 6 months; secondary outcomes after 6 and 9 months’ follow-up: quality of life, functioning, medication adherence, and so on.
Results: At baseline, a high proportion of patients had appropriate to mildly inappropriate prescriptions (MAI 0–5 points: n=350 patients). Randomisation revealed balanced groups (IG: 36 practices/252 patients; CG: 36/253). Intervention had no significant effect on primary outcome: mean MAI sum scores decreased by 0.3 points in IG and 0.8 points in CG, resulting in a non-significant adjusted mean difference of 0.7 (95% CI −0.2 to 1.6) points in favour of CG. Secondary outcomes showed non-significant changes (quality of life slightly improved in IG but continued to decline in CG) or remained stable (functioning, medication adherence).
Conclusions: The intervention had no significant effects. Many patients already received appropriate prescriptions and enjoyed good quality of life and functional status. We can therefore conclude that in our study, there was not enough scope for improvement.
Trial registration number: ISRCTN99526053. NCT01171339; Results.
Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture
(2017)
AIM: To investigate presence and extent of eosinophilic cholangitis (EC) as well as IgG4-related disease in patients with indeterminate biliary stricture (IBS).
METHODS: All patients with diagnosis of sclerosing cholangitis (SC) and histopathological samples such as biopsies or surgical specimens at University Hospital Frankfurt from 2005-2015 were included. Histopathological diagnoses as well as further clinical course were reviewed. Tissue samples of patients without definite diagnosis after complete diagnostic work-up were reviewed regarding presence of eosinophilic infiltration and IgG4 positive plasma cells. Eosinophilic infiltration was as well assessed in a control group of liver transplant donors and patients with primary sclerosing cholangitis.
RESULTS: one hundred and thirty-five patients with SC were included. In 10/135 (13.5%) patients, no potential cause of IBS could be identified after complete diagnostic work-up and further clinical course. After histopathological review, a post-hoc diagnosis of EC was established in three patients resulting in a prevalence of 2.2% (3/135) of all patients with SC as well as 30% (3/10) of patients, where no cause of IBS was identified. 2/3 patients with post-hoc diagnosis of EC underwent surgical resection with suspicion for malignancy. Diagnosis of IgG4-related cholangitis was observed in 7/135 patients (5.1%), whereas 3 cases were discovered in post-hoc analysis. 6/7 cases with IgG4-related cholangitis (85.7%) presented with eosinophilic infiltration in addition to IgG4 positive plasma cells. There was no patient with eosinophilic infiltration in the control group of liver transplant donors (n = 27) and patients with primary sclerosing cholangitis (n = 14).
CONCLUSION: EC is an underdiagnosed benign etiology of SC and IBS, which has to be considered in differential diagnosis of IBS.
Event-by-event fluctuations of the mean transverse momentum of charged particles produced in pp collisions at s√ = 0.9, 2.76 and 7 TeV, and Pb-Pb collisions at sNN−−−−√ = 2.76 TeV are studied as a function of the charged-particle multiplicity using the ALICE detector at the LHC. Dynamical fluctuations indicative of correlated particle emission are observed in all systems. The results in pp collisions show little dependence on collision energy. The Monte Carlo event generators PYTHIA and PHOJET are in qualitative agreement with the data. Peripheral Pb-Pb data exhibit a similar multiplicity dependence as that observed in pp. In central Pb-Pb, the results deviate from this trend, featuring a significant reduction of the fluctuation strength. The results in Pb--Pb are in qualitative agreement with previous measurements in Au-Au at lower collision energies and with expectations from models that incorporate collective phenomena.
The strength of forward-backward (FB) multiplicity correlations is measured by the ALICE detector in proton-proton (pp) collisions at s√=0.9, 2.76 and 7 TeV. The measurement is performed in the central pseudorapidity region (|η|<0.8) for the transverse momentum pT>0.3 GeV/c. Two separate pseudorapidity windows of width (δη) ranging from 0.2 to 0.8 are chosen symmetrically around η=0. The multiplicity correlation strength (bcor) is studied as a function of the pseudorapidity gap (ηgap) between the two windows as well as the width of these windows. The correlation strength is found to decrease with increasing ηgap and shows a non-linear increase with δη. A sizable increase of the correlation strength with the collision energy, which cannot be explained exclusively by the increase of the mean multiplicity inside the windows, is observed. The correlation coefficient is also measured for multiplicities in different configurations of two azimuthal sectors selected within the symmetric FB η-windows. Two different contributions, the short-range (SR) and the long-range (LR), are observed. The energy dependence of bcor is found to be weak for the SR component while it is strong for the LR component. Moreover, the correlation coefficient is studied for particles belonging to various transverse momentum intervals chosen to have the same mean multiplicity. Both SR and LR contributions to bcor are found to increase with pT in this case. Results are compared to PYTHIA and PHOJET event generators and to a string-based phenomenological model. The observed dependencies of bcor add new constraints on phenomenological models.
The strength of forward-backward (FB) multiplicity correlations is measured by the ALICE detector in proton-proton (pp) collisions at s√=0.9, 2.76 and 7 TeV. The measurement is performed in the central pseudorapidity region (|η|<0.8) for the transverse momentum pT>0.3 GeV/c. Two separate pseudorapidity windows of width (δη) ranging from 0.2 to 0.8 are chosen symmetrically around η=0. The multiplicity correlation strength (bcor) is studied as a function of the pseudorapidity gap (ηgap) between the two windows as well as the width of these windows. The correlation strength is found to decrease with increasing ηgap and shows a non-linear increase with δη. A sizable increase of the correlation strength with the collision energy, which cannot be explained exclusively by the increase of the mean multiplicity inside the windows, is observed. The correlation coefficient is also measured for multiplicities in different configurations of two azimuthal sectors selected within the symmetric FB η-windows. Two different contributions, the short-range (SR) and the long-range (LR), are observed. The energy dependence of bcor is found to be weak for the SR component while it is strong for the LR component. Moreover, the correlation coefficient is studied for particles belonging to various transverse momentum intervals chosen to have the same mean multiplicity. Both SR and LR contributions to bcor are found to increase with pT in this case. Results are compared to PYTHIA and PHOJET event generators and to a string-based phenomenological model. The observed dependencies of bcor add new constraints on phenomenological models.
The strength of forward-backward (FB) multiplicity correlations is measured by the ALICE detector in proton-proton (pp) collisions at s√=0.9, 2.76 and 7 TeV. The measurement is performed in the central pseudorapidity region (|η|<0.8) for the transverse momentum pT>0.3 GeV/c. Two separate pseudorapidity windows of width (δη) ranging from 0.2 to 0.8 are chosen symmetrically around η=0. The multiplicity correlation strength (bcor) is studied as a function of the pseudorapidity gap (ηgap) between the two windows as well as the width of these windows. The correlation strength is found to decrease with increasing ηgap and shows a non-linear increase with δη. A sizable increase of the correlation strength with the collision energy, which cannot be explained exclusively by the increase of the mean multiplicity inside the windows, is observed. The correlation coefficient is also measured for multiplicities in different configurations of two azimuthal sectors selected within the symmetric FB η-windows. Two different contributions, the short-range (SR) and the long-range (LR), are observed. The energy dependence of bcor is found to be weak for the SR component while it is strong for the LR component. Moreover, the correlation coefficient is studied for particles belonging to various transverse momentum intervals chosen to have the same mean multiplicity. Both SR and LR contributions to bcor are found to increase with pT in this case. Results are compared to PYTHIA and PHOJET event generators and to a string-based phenomenological model. The observed dependencies of bcor add new constraints on phenomenological models.
Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF).
Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.
Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.
Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors
(2018)
Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9–34 (mean 22). The degree of common (0–94%) and private mutations per sample was strongly varying (6–100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted.
Background: Patients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care.
Methods: A cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (>=70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by 30% or more.
Results: Data from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%.
Conclusions: A multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices.
Rationale: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production.
Methods: TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91phox-/-), myeloperoxidase-deficient (MPO-/-), and inducible nitric oxide synthase-deficient (iNOS-/-) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production in vivo by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive ex vivo analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences.
Results: The in vivo L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91phox-/- mice, up to 90 % decreased ROS/RNS production in the ears of MPO-/- mice and unaffected ROS/RNS production in the ears of iNOS-/- mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our in vivo L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91phox-/- mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91phox-/- mice with chronic DTHR, while the inflamed ears of MPO-/- mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91phox-/- mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR.
Conclusions: MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.
Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group’s cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The “ex-novo” occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies’ positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.
An improved method for isolation of yeast m utants auxotrophic for 5′-dTM P is presented. The procedure employs the two folic acid antagonists am inopterin and sulfanilam ide (SAA). Selectiveness of the procedure depends on concentration of SAA and time of incubation.
44 mutants auxotrophic and 3 conditionally auxotrophic for 5′-dTMP were isolated. All belong to one complementation group. The corresponding gene was designated TMP1. Tetrad dissection revealed its chromosomal nature. TMP1 is not closely linked to the genes ADE2,, LEU1, ARG 4, ILV2, HIS5, LYS1 and the mating type locus. With the centromere-linked genes ARG4 and LEU1 I gene TMP1 exhibited second division segregation frequencies of 0.42 and 0.53 respectively, indicative of centromere-linkage.
Strains auxotrophic and conditionally auxotrophic for 5′-dTM P were all respiratory deficient (petite). Genetical analysis indicates that the petite phenotype is due to loss of the rho factor in cells harbouring either tmp1 or tmp1ts alleles.
A screening procedure is presented which allows the isolation of yeast mutants (typ tlr) with highly efficient utilization of exogenous deoxythymidine-5′-monophosphate (5′-dTMP) (>50% ). Data are given concerning the phenomenon of 5′-dTMP utilization in general: (i) The ability of S. cerevisiae to incorporate exogenous 5′-dTMP was found to already be a wild type feature of this yeast, i. e. apparently not to be due to any mutation such as typ , tup, tmp per or tum. Consequently these mutations are interpreted as amplifiers of a pre-given wild type potency. So far eight stages of 5′-dTMP utilization were detected as classified by the optimal 5′-dTMP requirement, with 5′-dTMP biosynthesis blocked, of the corresponding mutant strains isolated. All of them fit well into a mathematical series of the type “2n × 1.5” (n = 0, 1, 2, … , 11), where the product term for n = 11 represents the 5′-dTMP requirement (μg/ml) of the best 5′-dTMP utilizing wild type strain found, (ii) Amplification of the 5′-dTMP utilizing potency obviously is due to any genetically determined alteration of the yeast 5′-dTMP uptaking principle itself or of physiological processes accompanying the monophosphate’s uptake, (iii) The functioning of 5′-dTMP uptake requires acidic (≦ pH 6) conditions in the yeast cell’s outer environment, (iv) Some yeast typ and typ tlr mutants were found to exhibit a more or less pronounced sensitivity towards exogenously offered 5′dTM P. The response of a sensitive strain towards inhibitory concentrations of the nucleotide apparently is co-conditioned by the presence or absence of thymidylate biosynthesis. With 5′-dTMP biosynthesis blocked the 5′-dTMP mediated inhibition is a permanent one and finally leads to the death of a cell. With a functioning thymidylate biosynthesis, in contrast, the inhibition is only temporary, (v) Yeast typ or typ tlr strains were observed to dephosphorylate exogenous 5′-dTMP to thymidine due to a phosphatase activity which cannot be eliminated at pH 7 + 70 mм inorganic phosphate conditions in the growth medium. This 5′-dTMP cleavage obviously occurs outside the cell and does not seem to be correlated both to the monophosphate’s uptake and to the phenomenon of 5′-dTMP sensitivity. The destruction of 5′-dTMP does not disturb (5′-dTMP) DNA-specific labelling.
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.
Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.
Long-range angular correlations on the near and away side in p–Pb collisions at √sNN=5.02 TeV
(2013)
Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p–Pb collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5<pT,assoc<pT,trig<4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and pT bins, and the widths show no significant evolution with event multiplicity or pT. These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations as well as hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a one-year period and full seasonal cycle (March 2014 - February 2015). The presented measurements provide a climatology of CCN properties for a characteristic central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The observed mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), elevated values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter κ exhibits remarkably little temporal variability: no pronounced diurnal cycles, weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modelling purposes, we compare different approaches of predicting CCN number concentration and present a novel parameterization, which allows accurate CCN predictions based on a small set of input data.
Size-resolved long-term measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a 1-year period and full seasonal cycle (March 2014–February 2015). The measurements provide a climatology of CCN properties characteristic of a remote central Amazonian rain forest site.
The CCN measurements were continuously cycled through 10 levels of supersaturation (S = 0.11 to 1.10 %) and span the aerosol particle size range from 20 to 245 nm. The mean critical diameters of CCN activation range from 43 nm at S = 1.10 % to 172 nm at S = 0.11 %. The particle hygroscopicity exhibits a pronounced size dependence with lower values for the Aitken mode (κAit = 0.14 ± 0.03), higher values for the accumulation mode (κAcc = 0.22 ± 0.05), and an overall mean value of κmean = 0.17 ± 0.06, consistent with high fractions of organic aerosol.
The hygroscopicity parameter, κ, exhibits remarkably little temporal variability: no pronounced diurnal cycles, only weak seasonal trends, and few short-term variations during long-range transport events. In contrast, the CCN number concentrations exhibit a pronounced seasonal cycle, tracking the pollution-related seasonality in total aerosol concentration. We find that the variability in the CCN concentrations in the central Amazon is mostly driven by aerosol particle number concentration and size distribution, while variations in aerosol hygroscopicity and chemical composition matter only during a few episodes.
For modeling purposes, we compare different approaches of predicting CCN number concentration and present a novel parametrization, which allows accurate CCN predictions based on a small set of input data.
Size-resolved measurements of atmospheric aerosol and cloud condensation nuclei (CCN) concentrations and hygroscopicity were conducted at the remote Amazon Tall Tower Observatory (ATTO) in the central Amazon Basin over a full seasonal cycle (Mar 2014–Feb 2015). In a companion part 1 paper, we presented an in-depth CCN characterization based on annually as well as seasonally averaged time intervals and discuss different parametrization strategies to represent the Amazonian CCN cycling in modelling studies (M. Pöhlker et al., 2016b). The present part 2 study analyzes the aerosol and CCN variability in original time resolution and, thus, resolves aerosol advection and transformation for the following case studies, which represent the most characteristic states of the Amazonian atmosphere:
1. Near-pristine (NP) conditions, defined as the absence of detectable black carbon (< 0.01 µg m−3), showed their highest occurrence (up to 30 %) in the wet season (i.e., Mar–May). On average, the NP episodes are characterized by a bimodal aerosol size distribution (strong Aitken mode: DAit = 70 nm, NAit = ~ 200 cm−3 vs. weaker accumulation mode: Dacc = 170 nm, Nacc = ~ 60 cm−3), a mostly organic particle composition, and relatively low hygroscopicity levels (κAit = 0.12 vs. κacc = 0.18). The NP CCN efficiency spectrum shows that the CCN population is sensitive to changes in supersaturation (S) over a wide S range.
2. Long-range transport (LRT) conditions frequently mix Saharan dust, African combustion smoke, and sea spray aerosols into the Amazonian wet season atmosphere. The LRT episodes (i.e., Feb–Apr) are characterized by an accumulation mode dominated size distribution (DAit = 80 nm, NAit = 120 cm−3 vs. Dacc = 180 nm, Nacc = 300 cm−3), a clearly increased abundance of dust and salt compounds, and relatively high hygroscopicity levels (κAit = 0.18, κacc = 0.34). The LRT CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
3. Biomass burning (BB) conditions dominate the Amazonian dry season. A selected characteristic BB episode shows a very strong accumulation mode (DAit = 70 nm, NAit = ~ 140 cm−3 vs. Dacc = 170 nm, Nacc = ~ 3400 cm−3), particles with very high organic fractions (> 90 %), and correspondingly low hygroscopicity levels (κAit = 0.14, κacc = 0.17). The BB CCN efficiency spectrum shows that the CCN population is highly sensitive to changes in S in the low S regime.
4. Mixed pollution conditions show the superposition of African (i.e., volcanic) and Amazonian (i.e., biomass burning) aerosol emissions during the dry season. The African aerosols showed a broad monomodal distribution (D = 130 nm, N = ~ 1300 cm−3), with very high sulfate fractions (20 %), and correspondingly high hygroscopicity (κAit = 0.14, κacc = 0.22). This was superimposed by fresh smoke from nearby fires with one strong mode (D = 113 nm, Nacc = ~ 2800 cm−3), an organic-dominated aerosol, and sharply decreased hygroscopicity (κAit = 0.10, κacc = 0.20). These conditions underline the rapidly changing pollution regimes with clear impacts on the aerosol and CCN properties.
Overall, this study provides detailed insights into the CCN cycling in relation to aerosol-cloud interaction in the vulnerable and climate-relevant Amazon region. The detailed analysis of aerosol and CCN key properties and particularly the extracted CCN efficiency spectra with the associated fit parameters provide a basis for an in-depth analysis of aerosol-cloud interaction in the Amazon and beyond.
Patients after orthopic liver transplantation (OLT) are at risk of developing graft dysfunction. Sphingolipids (SL’s) have been identified to play a pivotal role in the regulation of hepatocellular apoptosis, inflammation and immunity. We aimed to investigate the serum SL profile in a prospective real-world cohort of post-OLT patients. From October 2015 until July 2016, 149 well-characterized post-OLT patients were analyzed. SL’s were assessed in serum probes via Liquid Chromatography/Tandem Mass Spectrometry. Twenty-nine (20%) patients had a biopsy proven graft rejection with decreased C20-ceramide (Cer) (p = 0.042), C18-dihydroceramide (DHC) (p = 0.022) and C24DHC (p = 0.060) levels. Furthermore, C18DHC (p = 0.044) and C24DHC (p = 0.011) were significantly down-regulated in patients with ischemic type biliary lesions (ITBL; n = 15; 10%). One-hundred and thirty-three patients (89%) have so far received tacrolimus as the main immunosuppressive agent with observed elevations of C14Cer (p = 0.052), C18Cer (p = 0.049) and C18:1Cer (p = 0.024). Hepatocellular carcinoma (HCC) pre-OLT was associated with increases in C24:1Cer (p = 0.024) and C24:1DHC (p = 0.024). In this large prospective cross-sectional study of patients, post-OLT serum levels of (very-)long chain (dihydro-)ceramides associate with graft rejection, ITBL, tacrolimus intake and HCC pre-OLT. Hence, serum SL’s may be indicative of graft complications. Further research is necessary to identify their diverse mechanistic role in regulating immunity and inflammation in patients post-OLT.