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In 2012 Georg Diez provoked a literary scandal with his review of Christian Kracht’s novel Imperium. Since then, almost ninety informed studies which show an ongoing academic interest in the book have been published. Many of these studies attempted to explain the apparently failing analogy between Hitler and Engelhardt that the novel claimed in an irritating manner. Nevertheless, none of them took an esoteric approach which Kracht himself suggested in an interview with Denis Scheck as a starting point for their analyses, although esoteric references seem to be an ignored constant in Kracht’s oeuvre since Tristesse Royale. Hence, by tracing this esoteric intertextuality in the whole of Kracht’s oeuvre and linking it to the references which Kracht makes to right-wing ideologies since Faserland, it will be shown that there actually does exist an analogy between Hitler and Engelhardt in Imperium which aims to deconstruct Hitler mythemes by ridiculizing Engelhardt. Furthermore, it will be demonstrated that the interrelations between Kracht’s texts create a rhizomatic network of intertextuality that dissolves the boarders between external references and self-references.
Loneliness and lack of social well-being are associated with adverse health outcomes and have increased during the COVID-19 pandemic. Smartphone communication data have been suggested to help monitor loneliness, but this requires further evidence. We investigated the informative value of smartphone communication app data for predicting subjective loneliness and social well-being in a sample of 364 participants ranging from 18 to 78 years of age (52.2% female; mean age = 42.54, SD = 13.22) derived from the CORONA HEALTH APP study from July to December 2020 in Germany. The participants experienced relatively high levels of loneliness and low social well-being during the time period characterized by the COVID-19 pandemic. Apart from positive associations with phone call use times, smartphone communication app use was associated with social well-being and loneliness only when considering the age of participants. Younger participants with higher use times tended to report less social well-being and higher loneliness, while the opposite association was found for older adults. Thus, the informative value of smartphone communication use time was rather small and became evident only in consideration of age. The results highlight the need for further investigations and the need to address several limitations in order to draw conclusions at the population level.
Conversational agents and smart speakers have grown in popularity offering a variety of options for use, which are available through intuitive speech operation. In contrast to the standard dyad of a single user and a device, voice-controlled operations can be observed by further attendees resulting in new, more social usage scenarios. Referring to the concept of ‘media equation’ and to research on the idea of ‘computers as social actors,’ which describes the potential of technology to trigger emotional reactions in users, this paper asks for the capacity of smart speakers to elicit empathy in observers of interactions. In a 2 × 2 online experiment, 140 participants watched a video of a man talking to an Amazon Echo either rudely or neutrally (factor 1), addressing it as ‘Alexa’ or ‘Computer’ (factor 2). Controlling for participants’ trait empathy, the rude treatment results in participants’ significantly higher ratings of empathy with the device, compared to the neutral treatment. The form of address had no significant effect. Results were independent of the participants’ gender and usage experience indicating a rather universal effect, which confirms the basic idea of the media equation. Implications for users, developers and researchers were discussed in the light of (future) omnipresent voice-based technology interaction scenarios.
Purpose
One therapy option for prostate cancer patients with bone metastases is the use of [\(^{223}\)Ra]RaCl\(_{2}\). The α-emitter \(^{223}\)Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [\(^{223}\)Ra]RaCl\(_{2}\).
Methods
Multiple blood samples from nine prostate cancer patients were collected before and after administration of [\(^{223}\)Ra]RaCl\(_{2}\), up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs.
Results
The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated.
Conclusion
The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from β-emitters based on damage geometry.
According to the Senegalesian scholar Felwine Sarr who conceives an African utopia in his programmatic essay Afrotopia (2016), this Afrotopos has already germinated in contemporary African literature. However, it still needs to be enquired to what extent the narrated topos of the street in Sarr’s own anthology 105 Rue Carnot (2011) has already realized the Afrotopos. In order to respond to this question, we would like to mobilise Michel Foucault’s concept of heterotopia, which elaborates on the interactions between truth production/knowledge, power and space, and permits us to conceive of «les lieux utopiques» (Foucault 2005: 40) as actually locatable on the map and real other places outside of all places (cf. Foucault 1994: 755). Thus, in the street, a different relationship between global North and South is founded, which becomes legible as an African «utopie localisée» (Foucault 2005: 41) that Sarr calls for in Afrotopia (2016).
Bis zum Jahr 2100 prognostiziert der Weltklimarat (IPCC 2021) einen Anstieg des Meeresspiegels von bis zu 63-101 cm gegenüber heutigen Wasserständen. Im Rahmen des Generalplans Küstenschutz Schleswig-Holstein(GKSH) soll als Klimafolgeanpassung eine Erhöhung und Profiländerung der meisten Nordseedeiche und Elbedeiche erfolgen (zusammen 363,3 km mit einer Vegetationsfläche von 3.500 ha). Diese Maßnahmen werden mit einem vollständigen Verlust der alten Deichvegetation einhergehen und zur Freisetzung von großen Mengen an CO₂ aus dem Bodenkohlenstoff führen. Die Seedeiche der Nordseeküste (262 km) zählen zu den artenreichen, semi-natürlichen und von Schafen beweideten Grasländern (Fläche von 2600 ha) in Schleswig-Holstein mit bis zu 18 Gras- und 64 zweikeim-blättrigen Blütenpflanzen und an die Vegetation gebundene 800-1000 Arten von Invertebraten (darunter 200 Käferarten). Auf die Außenböschung dringen Pflanzen der Salzwiesengesellschaften vor. Die steileren, wärmeexponierten (überwiegend nach Osten und Süden ausgerichtet) und durch Vertritt lückigen Innenböschungen der Seedeiche sind wertvolle Refugien wärmeliebender, konkurrenzschwacher Arten von Magerstandorten und Trittgesellschaften wie die folgenden mediterran-subatlantischen Arten: Knotenklettenkerbel (Torilis nodosa), Zwergklee/Armblütiger Klee (Trifolium micranthum) und Vogelfußklee (Trifolium ornithopodioides). Für die Erhaltung beider Kleearten (die aktuelle Verbreitung wird dokumentiert) besitzt Schleswig-Holstein eine nationale und nordwest-europäisch-kontinentale Verantwortlichkeit. Folgende Maßnahmen zum Schutz der reichhaltigen Deichvegetation und Teilen seiner Invertebratenfauna bei der Deichverstärkung im Rahmen des GKSH werden vorgeschlagen: 1. Abheben der Grasnarbe mit Wurzelraum und zeitnahe Wiederverlegung der alten Grasnarbe (Soden) auf das neue Deichprofil; das ist auch wichtig zum Erhalt des Bodenkohlenstoffs (Klimaschutz). 2. Einsaat von neuen Deichprofilen mit Saatgut von artenreichen Deichabschnitten. 3. Aufnahme substanzieller Forschungsprogramme/Forschungsförderung zur Ökologie der Seedeiche. Weiterhin sollte auf den Einsatz von Herbiziden auf Deichen zur Bekämpfung von Disteln verzichtet werden.
Die Corona-Pandemie hat dem Aktienrecht einen unerwarteten Modernisierungsschub verliehen. Der Gesetzgeber schuf in Windeseile eine zeitlich begrenzte rechtliche Grundlage für die rein virtuelle Hauptversammlung. Die Gesellschaften haben diese neue rechtliche und technische Herausforderung gut gemeistert. Das legt die Frage nahe, ob der Gesetzgeber nicht auch für die Zukunft eine rein virtuelle Hauptversammlung in rechtlich abgesicherter Form ermöglichen sollte. Dabei müssen die Rechte der Aktionäre umfassend gewahrt bleiben. Zugleich sollten die Defizite der Hauptversammlungskultur behoben werden, die heute nur noch in Grenzen als Forum der freien Diskussion zwischen Aktionären und Unternehmensleitung angesehen werden kann. Das Beste aus zwei Welten liegt nach der hier entfalteten Konzeption in einer hybriden Versammlung, die eine Präsenzversammlung mit qualifizierten Teilnahmevoraussetzungen und eine elektronische Teilnahme aller übrigen Aktionäre ermöglicht.
In this communication, we demonstrate a novel approach to prepare a discrete dimer of chiral phthalocyanine (Pc) by exploiting the flexible molecular geometry of helicenes, which enables structural interlocking and strong aggregation tendency of Pcs. Synthesized [7]helicene-Pc hybrid molecular structure, zinc-[7]helicenocyanine (Zn-7HPc), exclusively forms a stable dimeric pair consisting of two homochiral molecules. The dimerization constants were estimated to be as high as 8.96×10\(^6\) M\(^{−1}\) and 3.42×107 M\(^{−1}\) in THF and DMSO, respectively, indicating remarkable stability of dimer. In addition, Zn\(^{-7}\)HPc exhibited chiral self-sorting behavior, which resulted in preferential formation of a homochiral dimer also in the racemic sample. Two phthalocyanine subunits in the dimeric form strongly communicate with each other as revealed by a large comproportionation constant and observation of an IV-CT band for the thermodynamically stable mixed-valence state.
Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.
Purpose
High myopic patients may develop strabismus due to globe dislocation out of the normal extraocular muscle cone. Surgical correction of this strabismus type is possible by joining the superior and lateral rectus muscles without the need for a scleral suture called the Yokoyama procedure. Data from large patient samples and the evaluation of a potential effect of an additional medial rectus recession (MRR) have been lacking so far.
Methods
We pooled retrospective patient data of 14 departments of ophthalmology in Germany and Switzerland and analysed determinants of postoperative results using multivariable regression models.
Results
We included 133 patients (mean age: 59.7 ± 13.4 years, surgery between 2008 and 2017) with a mean preoperative esotropia (both Yokoyama with and without MRR) of 23.8°±4.6°. The angle of preoperative esotropia increased with age. The postoperative esotropia was 8.7° ± 9.9°, and six patients were overcorrected. While preoperative esotropia was highly associated with postoperative results, we found no association of additional MRR with any of our postoperative outcome measures. The Yokoyama procedure had a higher absolute effect in patients with higher preoperative esotropia.
Conclusion
Our study confirms the positive effect of the Yokoyama procedure on strabismus due to high myopia in large‐scale real‐world data. In some cases, MRR may be needed because of muscle contracture, although additional MRR statistically did not affect the postoperative outcome. In patients with bilateral high myopic strabismus, correction of both eyes seems beneficial. The effect size of the Yokoyama procedure appears to be mainly driven by preoperative esotropia.
Objective
To examine the efficacy of reminder e-mails to continue yoga therapy on practice frequency and fatigue in cancer patients and long-term effects of yoga on fatigue, depression, and quality of life.
Methology
One hundred two cancer patients who completed an 8-week yoga therapy were randomly allocated to two groups: reminder (N = 51) vs. no-reminder group (N = 51). After completing yoga therapy, the reminder group received weekly e-mails for 24 weeks, which reminded them of practicing yoga, whereas the no-reminder group did not. Primary outcomes were fatigue and practice frequency, and long-term outcomes were fatigue, depression, and quality of life. Data were assessed using questionnaires after yoga therapy (T1) and 6 months after completing yoga therapy (T2).
Result
A significantly stronger reduction of general (p = 0.038, d = 0.42) and emotional fatigue (p = 0.004, d = 0.59) and a higher increase of practice frequency (p = 0.015, d = 0.52) between T1 and T2 were found for the reminder group compared to the no-reminder group. In the mediation model, practice frequency as a mediator partially explained the changes in emotional fatigue (indirect effect B = - 0.10). Long-term effects of yoga therapy regarding fatigue, depression, and quality of life were found (F > 7.46, p < 0.001, d > 0.54).
Conclusion
Weekly reminder e-mails after yoga therapy can positively affect general and emotional fatigue and help cancer patients with fatigue establish a regular yoga practice at home. However, higher practice frequency did not lead to higher physical or cognitive fatigue improvement, suggesting other factors that mediate efficacy on physical or cognitive fatigue, such as mindfulness or side effects of therapy.
Purpose
Examine the effects of an 8-week yoga therapy on fatigue in patients with different types of cancer.
Methods
A total of 173 cancer patients suffering from mild to severe fatigue were randomly allocated to yoga intervention (n = 84) (IG) versus waitlist control group (CG) (n = 88). Yoga therapy consisted of eight weekly sessions with 60 min each. The primary outcome was self-reported fatigue symptoms. Secondary outcomes were symptoms of depression and quality of life (QoL). Data were assessed using questionnaires before (T0) and after yoga therapy for IG versus waiting period for CG (T1).
Results
A stronger reduction of general fatigue (P = .033), physical fatigue (P = .048), and depression (P < .001) as well as a stronger increase in QoL (P = .002) was found for patients who attended 7 or 8 sessions compared with controls. Within the yoga group, both higher attendance rate and lower T0-fatigue were significant predictors of lower T1-fatigue (P ≤ .001). Exploratory results revealed that women with breast cancer report a higher reduction of fatigue than women with other types of cancer (P = .016) after yoga therapy.
Conclusion
The findings support the assumption that yoga therapy is useful to reduce cancer-related fatigue, especially for the physical aspects of fatigue. Women with breast cancer seem to benefit most, and higher attendance rate results in greater reduction of fatigue.
Trial registration
German Clinical Trials Register DRKS00016034
Many species synchronize reproductive behavior with a particular phase of the lunar cycle to increase reproductive success. In humans, a lunar influence on reproductive behavior remains controversial, although the human menstrual cycle has a period close to that of the lunar cycle. Here, we analyzed long-term menstrual recordings of individual women with distinct methods for biological rhythm analysis. We show that women’s menstrual cycles with a period longer than 27 days were intermittently synchronous with the Moon’s luminance and/or gravimetric cycles. With age and upon exposure to artificial nocturnal light, menstrual cycles shortened and lost this synchrony. We hypothesize that in ancient times, human reproductive behavior was synchronous with the Moon but that our modern lifestyles have changed reproductive physiology and behavior.
Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [\(^{68}\)Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [\(^{68}\)Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.
Wilms' tumor primary cells display potent immunoregulatory properties on NK cells and macrophages
(2021)
The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56\(^+\)/CD133\(^−\)) or an epithelial (CD56\(^−\)/CD133\(^+\)) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.
Purpose
This study investigates the redislocation rate and functional outcome at a minimum follow-up of five years after medial patellofemoral ligament (MPFL) reconstruction with soft tissue patellar fixation for patella instability.
Methods
Patients were retrospectively identified and knees were evaluated for trochlea dysplasia according to Dejour, for presence of patella alta and for presence of cartilage lesion at surgery. At a minimum follow-up of five years, information about an incident of redislocation was obtained. Kujala, Lysholm, and Tegner questionnaires as well as range of motion were used to measure functional outcome.
Results
Eighty-nine knees were included. Follow-up rate for redislocation was 79.8% and for functional outcome 58.4%. After a mean follow-up of 5.8 years, the redislocation rate was 5.6%. There was significant improvement of the Kujala score (68.8 to 88.2, p = 0.000) and of the Lysholm score (71.3 to 88.4, p = 0.000). Range of motion at follow-up was 149.0° (115–165). 77.5% of the knees had patella alta and 52.9% trochlear dysplasia types B, C, or D. Patellar cartilage legions were present in 54.2%. Redislocations occurred in knees with trochlear dysplasia type C in combination with patella alta.
Conclusion
MPFL reconstruction with soft tissue patellar fixation leads to significant improvement of knee function and low midterm redislocation rate. Patients with high-grade trochlear dysplasia should be considered for additional osseous correction.
Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease
(2021)
The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95–1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85–0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95–1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83–1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55–0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57–0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.
A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.
The extinction of species is a non‐random process, and understanding why some species are more likely to go extinct than others is critical for conservation efforts. Functional trait‐based approaches offer a promising tool to achieve this goal. In forests, deadwood‐dependent (saproxylic) beetles comprise a major part of threatened species, but analyses of their extinction risk have been hindered by the availability of suitable morphological traits.
To better understand the mechanisms underlying extinction in insects, we investigated the relationships between morphological features and the extinction risk of saproxylic beetles. Specifically, we hypothesised that species darker in colour, with a larger and rounder body, a lower mobility, lower sensory perception and more robust mandibles are at higher risk.
We first developed a protocol for morphological trait measurements and present a database of 37 traits for 1,157 European saproxylic beetle species. Based on 13 selected, independent traits characterising aspects of colour, body shape, locomotion, sensory perception and foraging, we used a proportional‐odds multiple linear mixed‐effects model to model the German Red List categories of 744 species as an ordinal index of extinction risk.
Six out of 13 traits correlated significantly with extinction risk. Larger species as well as species with a broad and round body had a higher extinction risk than small, slim and flattened species. Species with short wings had a higher extinction risk than those with long wings. On the contrary, extinction risk increased with decreasing wing load and with higher mandibular aspect ratio (shorter and more robust mandibles).
Our study provides new insights into how morphological traits, beyond the widely used body size, determine the extinction risk of saproxylic beetles. Moreover, our approach shows that the morphological characteristics of beetles can be comprehensively represented by a selection of 13 traits. We recommend them as a starting point for functional analyses in the rapidly growing field of ecological and conservation studies of deadwood.
Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.
Farmland tree cultivation is considered an important option for enhancing wood production. In South India, the native leaf-deciduous tree species Melia dubia is popular for short-rotation plantations. Across a rainfall gradient from 420 to 2170 mm year\(^{–1}\), we studied 186 farmland woodlots between one and nine years in age. The objectives were to identify the main factors controlling aboveground biomass (AGB) and growth rates. A power-law growth model predicts an average stand-level AGB of 93.8 Mg ha\(^{–1}\) for nine-year-old woodlots. The resulting average annual AGB increment over the length of the rotation cycle is 10.4 Mg ha\(^{–1}\) year\(^{–1}\), which falls within the range reported for other tropical tree plantations. When expressing the parameters of the growth model as functions of management, climate and soil variables, it explains 65% of the variance in AGB. The results indicate that water availability is the main driver of the growth of M. dubia. Compared to the effects of water availability, the effects of soil nutrients are 26% to 60% smaller. We conclude that because of its high biomass accumulation rates in farm forestry, M. dubia is a promising candidate for short-rotation plantations in South India and beyond.
The article starts with the etymology of the words Vorlesung („lecture“) and Hörsaal (“lecture hall”). On the one hand, it turns out that the two expressions are deeply anchored in the history of the old Latin scientific language. They transmit Latin structures and perspectives in German neologisms. On the other hand, the two words arose exactly at the time when the sciences were moving from Latin to German, thus distancing themselves from the traditional forms of Latin scholarship. In this light, they exemplify an epochal change in the history of the German language, but at the same time they represent a great European continuity. Against this background, the two words can be interpreted as symptomatic words associated with the Enlightenment’s confident outlook on the future relationship between science and society. Further corpus linguistic surveys also show how productively the two words appear in word formation processes. In particular, these surveys show by way of example that and how German standard language has benefited from the emergence of German academic language.
Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{−/−}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{−/−}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{−/−}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression.
(1) Background: Evidence has accumulated that patients with anorexia nervosa (AN) are at higher risk for vitamin D deficiency than healthy controls. In epidemiologic studies, low 25(OH) vitamin D (25(OH)D) levels were associated with depression. This study analyzed the relationship between 25(OH)D serum levels in adolescent patients and AN and depressive symptoms over the course of treatment. (2) Methods: 25(OH)D levels and depressive symptoms were analyzed in 93 adolescent (in-)patients with AN from the Anorexia Nervosa Day patient versus Inpatient (ANDI) multicenter trial at clinic admission, discharge, and 1 year follow up. Mixed regression models were used to analyze the relationship between 25(OH)D levels and depressive symptoms assessed by the Beck Depression Inventory (BDI-II). (3) Results: Although mean 25(OH)D levels constantly remained in recommended ranges (≥50 nmol/L) during AN treatment, levels decreased from (in)patient admission to 1 year follow up. Levels of 25(OH)D were neither cross-sectionally, prospectively, nor longitudinally associated with the BDI-II score. (4) Conclusions: This study did not confirm that 25(OH)D levels are associated with depressive symptoms in patients with AN. However, increasing risks of vitamin D deficiency over the course of AN treatment indicate that clinicians should monitor 25(OH)D levels.
Strains of the food-borne pathogen Listeria (L.) monocytogenes have diverse virulence potential. This study focused on the virulence of three outbreak strains: the CC1 strain PF49 (serovar 4b) from a cheese-associated outbreak in Switzerland, the clinical CC2 strain F80594 (serovar 4b), and strain G6006 (CC3, serovar 1/2a), responsible for a large gastroenteritis outbreak in the USA due to chocolate milk. We analysed the genomes and characterized the virulence in vitro and in vivo. Whole-genome sequencing revealed a high conservation of the major virulence genes. Minor deviations of the gene contents were found in the autolysins Ami, Auto, and IspC. Moreover, different ActA variants were present. Strain PF49 and F80594 showed prolonged survival in the liver of infected mice. Invasion and intracellular proliferation were similar for all strains, but the CC1 and CC2 strains showed increased spreading in intestinal epithelial Caco2 cells compared to strain G6006. Overall, this study revealed long-term survival of serovar 4b strains F80594 and PF49 in the liver of mice. Future work will be needed to determine the genes and molecular mechanism behind the long-term survival of L. monocytogenes strains in organs.
Virtual online training has emerged as one of the top 20 worldwide fitness trends for 2021 and continues to develop rapidly. Although this allows the cycling community to engage in virtual training and competition, critical evaluation of virtual training platforms is limited. Here, we discuss the strengths, weaknesses, opportunities and threats associated with virtual training technology and cycling in an attempt to enhance awareness of such aspects. Strengths include immersive worlds, innovative drafting mechanics, and versatility. Weaknesses include questionable data accuracy, inadequate strength and reliability of power-speed algorithms. Opportunities exist for expanding strategic partnerships with major cycling races, brands, and sponsors and improving user experience with the addition of video capture and “e-coaching.” Threats are present in the form of cheating during competition, and a lack of uptake and acceptance by a broader community.
The differentiation of human induced pluripotent stem cells (hiPSCs) into specific cell types for disease modeling and restorative therapies is a key research agenda and offers the possibility to obtain patient-specific cells of interest for a wide range of diseases. Basal forebrain cholinergic neurons (BFCNs) play a particular role in the pathophysiology of Alzheimer’s dementia and isolated dystonias. In this work, various directed differentiation protocols based on monolayer neural induction were tested for their effectiveness in promoting a ventral telencephalic phenotype and generating BFCN. Ventralizing factors [i.e., purmorphamine and Sonic hedgehog (SHH)] were applied at different time points, time intervals, and concentrations. In addition, caudal identity was prevented by the use of a small molecule XAV-939 that inhibits the Wnt-pathway. After patterning, gene expression profiles were analyzed by quantitative PCR (qPCR). Rostro-ventral patterning is most effective when initiated simultaneously with neural induction. The most promising combination of patterning factors was 0.5 μM of purmorphamine and 1 μM of XAV-939, which induces the highest expression of transcription factors specific for the medial ganglionic eminence, the source of GABAergic inter- and cholinergic neurons in the telencephalon. Upon maturation of cells, the immune phenotype, as well as electrophysiological properties were investigated showing the presence of marker proteins specific for BFCN (choline acetyltransferase, ISL1, p75, and NKX2.1) and GABAergic neurons. Moreover, a considerable fraction of measured cells displayed mature electrophysiological properties. Synaptic boutons containing the vesicular acetylcholine transporter (VACHT) could be observed in the vicinity of the cells. This work will help to generate basal forebrain interneurons from hiPSCs, providing a promising platform for modeling neurological diseases, such as Alzheimer’s disease or Dystonia.
Freely available satellite data at Google Earth Engine (GEE) cloud platform enables vegetation phenology analysis across different scales very efficiently. We evaluated seasonal and annual phenology of the old-growth Hyrcanian forests (HF) of northern Iran covering an area of ca. 1.9 million ha, and also focused on 15 UNESCO World Heritage Sites. We extracted bi-weekly MODIS-NDVI between 2017 and 2020 in GEE, which was used to identify the range of NDVI between two temporal stages. Then, changes in phenology and growth were analyzed by Sentinel 2-derived Temporal Normalized Phenology Index. We modelled between seasonal phenology and growth by additionally considering elevation, surface temperature, and monthly precipitation. Results indicated considerable difference in onset of forests along the longitudinal gradient of the HF. Faster growth was observed in low- and uplands of the western zone, whereas it was lower in both the mid-elevations and the western outskirts. Longitudinal range was a major driver of vegetation growth, to which environmental factors also differently but significantly contributed (p < 0.0001) along the west-east gradient. Our study developed at GEE provides a benchmark to examine the effects of environmental parameters on the vegetation growth of HF, which cover mountainous areas with partly no or limited accessibility.
The clinical and preclinical research of ischemic strokes (IS) is becoming increasingly comprehensive, especially with the emerging evidence of complex thrombotic and inflammatory interactions. Within these, the blood brain barrier (BBB) plays an important role in regulating the cellular interactions at the vascular interface and is therefore the object of many IS-related questions. Consequently, valid, economic and responsible methods to define BBB integrity are necessary. Therefore, we compared the three ex-vivo setups albumin Western blot (WB), IgG WB and albumin intensity measurement (AIM) with regard to validity as well as temporal and economic efficacy. While the informative value of the three methods correlated significantly, the efficacy of the IgG WB dominated.
Land Surface Temperature (LST) is an important parameter for tracing the impact of changing climatic conditions on our environment. Describing the interface between long- and shortwave radiation fluxes, as well as between turbulent heat fluxes and the ground heat flux, LST plays a crucial role in the global heat balance. Satellite-derived LST is an indispensable tool for monitoring these changes consistently over large areas and for long time periods. Data from the AVHRR (Advanced Very High-Resolution Radiometer) sensors have been available since the early 1980s. In the TIMELINE project, LST is derived for the entire operating period of AVHRR sensors over Europe at a 1 km spatial resolution. In this study, we present the validation results for the TIMELINE AVHRR daytime LST. The validation approach consists of an assessment of the temporal consistency of the AVHRR LST time series, an inter-comparison between AVHRR LST and in situ LST, and a comparison of the AVHRR LST product with concurrent MODIS (Moderate Resolution Imaging Spectroradiometer) LST. The results indicate the successful derivation of stable LST time series from multi-decadal AVHRR data. The validation results were investigated regarding different LST, TCWV and VA, as well as land cover classes. The comparisons between the TIMELINE LST product and the reference datasets show seasonal and land cover-related patterns. The LST level was found to be the most determinative factor of the error. On average, an absolute deviation of the AVHRR LST by 1.83 K from in situ LST, as well as a difference of 2.34 K from the MODIS product, was observed.
Crowdsourced network measurements (CNMs) are becoming increasingly popular as they assess the performance of a mobile network from the end user's perspective on a large scale. Here, network measurements are performed directly on the end-users' devices, thus taking advantage of the real-world conditions end-users encounter. However, this type of uncontrolled measurement raises questions about its validity and reliability. The problem lies in the nature of this type of data collection. In CNMs, mobile network subscribers are involved to a large extent in the measurement process, and collect data themselves for the operator. The collection of data on user devices in arbitrary locations and at uncontrolled times requires means to ensure validity and reliability. To address this issue, our paper defines concepts and guidelines for analyzing the precision of CNMs; specifically, the number of measurements required to make valid statements. In addition to the formal definition of the aspect, we illustrate the problem and use an extensive sample data set to show possible assessment approaches. This data set consists of more than 20.4 million crowdsourced mobile measurements from across France, measured by a commercial data provider.
Purpose
The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size.
Methods
Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated.
Results
Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05).
Conclusion
No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.
Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
This paper examines situations where two vertically integrated firms consider supplying an input to an independent downstream competitor via privately observed contracts. We identify equilibria where competition in the upstream market emerges—the downstream competitor gets supplied—as well as when the downstream firm does not receive the input and is excluded from the market. The likelihood of the outcome in which the downstream firm does not get supplied depends not only on demand parameters, but also on contractual flexibility and observability. We show that when contracts are unobservable, downstream entry will occur less often. Furthermore, our results suggest that permitting contracts that enable the contracting parties to coordinate their behavior in the downstream market may improve welfare by increasing the likelihood that the downstream firm is supplied.
Uplink vs. Downlink: Machine Learning-Based Quality Prediction for HTTP Adaptive Video Streaming
(2021)
Streaming video is responsible for the bulk of Internet traffic these days. For this reason, Internet providers and network operators try to make predictions and assessments about the streaming quality for an end user. Current monitoring solutions are based on a variety of different machine learning approaches. The challenge for providers and operators nowadays is that existing approaches require large amounts of data. In this work, the most relevant quality of experience metrics, i.e., the initial playback delay, the video streaming quality, video quality changes, and video rebuffering events, are examined using a voluminous data set of more than 13,000 YouTube video streaming runs that were collected with the native YouTube mobile app. Three Machine Learning models are developed and compared to estimate playback behavior based on uplink request information. The main focus has been on developing a lightweight approach using as few features and as little data as possible, while maintaining state-of-the-art performance.
Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results.
Update Breast Cancer 2020 Part 5 – Moving Therapies From Advanced to Early Breast Cancer Patients
(2021)
In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2−/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020.
Hintergrund
Die E‑Zigarette erfreut sich in den letzten Jahren zunehmender Beliebtheit. Die Frage nach der Toxizität ist jedoch noch nicht eindeutig geklärt, und es herrscht global Unsicherheit im Umgang mit der E‑Zigarette.
Ziel
Ziel der vorliegenden Arbeit war es, Propylenglykol, ein Hauptbestandteil der Liquide, in Bezug auf mögliche akute Entzündungsreaktionen, zyto- und genotoxische Auswirkungen auf humane Nasenschleimhautzellen zu untersuchen.
Material und Methoden
Die Nasenschleimhautzellen wurden von zehn Probanden im Air-Liquid-Interface kultiviert und anschließend mit unterschiedlichen Konzentrationen des Propylenglykols bedampft. Die Analyse erfolgte mittels Trypanblau-Test, Comet-Assay, Mikrokerntest und IL-6- und IL-8-Sandwich-ELISA.
Ergebnis
Der Trypanblau-Test zeigte keine Reduktion der Vitalität. Im Sandwich-ELISA konnte kein Anstieg der IL-6- und IL-8-Konzentrationen nachgewiesen werden. Im Comet-Assay zeigte das Olive Tail Moment eine Schädigung im Vergleich zur Negativkontrolle in allen untersuchten Konzentrationen. Zudem zeigte sich eine dosisabhängige Schädigung. Im Mikrokerntest konnte ein Unterschied zwischen dem Reinstoff und der Negativkontrolle gefunden werden.
Schlussfolgerung
Es zeigten sich möglicherweise reparable DNS-Schädigungen im Comet-Assay. Im Mikrokerntest konnten diese nur in der Reinstoffkonzentration bestätigt werden. Es sollte ein restriktiver Umgang mit der E‑Zigarette erfolgen, bis insbesondere Langzeitstudien vorliegen. Zudem ist eine eindeutige Deklaration der Inhaltsstoffe der Liquide durch die Hersteller zu fordern, um weitergehende Schädigungspotenziale untersuchen zu können.
The bounded input bounded output (BIBO) stability for a nonlinear Caputo fractional system with time‐varying bounded delay and nonlinear output is studied. Utilizing the Razumikhin method, Lyapunov functions and appropriate fractional derivatives of Lyapunov functions some new bounded input bounded output stability criteria are derived. Also, explicit and independent on the initial time bounds of the output are provided. Uniform BIBO stability and uniform BIBO stability with input threshold are studied. A numerical simulation is carried out to show the system's dynamic response, and demonstrate the effectiveness of our theoretical results.
African trypanosomes cause sleeping sickness in humans and nagana in cattle. These unicellular parasites are transmitted by the bloodsucking tsetse fly. In the mammalian host’s circulation, proliferating slender stage cells differentiate into cell cycle-arrested stumpy stage cells when they reach high population densities. This stage transition is thought to fulfil two main functions: first, it auto-regulates the parasite load in the host; second, the stumpy stage is regarded as the only stage capable of successful vector transmission. Here, we show that proliferating slender stage trypanosomes express the mRNA and protein of a known stumpy stage marker, complete the complex life cycle in the fly as successfully as the stumpy stage, and require only a single parasite for productive infection. These findings suggest a reassessment of the traditional view of the trypanosome life cycle. They may also provide a solution to a long-lasting paradox, namely the successful transmission of parasites in chronic infections, despite low parasitemia.
Oligophenyleneethynylenes (OPEs) are prominent building blocks with exciting optical and supramolecular properties. However, their generally small spectroscopic changes upon aggregation make the analysis of their self-assembly challenging, especially in the absence of additional hydrogen bonds. Herein, by investigating a series of OPEs of increasing size, we have unravelled the role of the conjugation length on the self-assembly properties of OPEs.
Soil salinity is an increasingly global problem which hampers plant growth and crop yield. Plant productivity depends on optimal water-use efficiency and photosynthetic capacity balanced by stomatal conductance. Whether and how stomatal behavior contributes to salt sensitivity or tolerance is currently unknown. This work identifies guard cell-specific signaling networks exerted by a salt-sensitive and salt-tolerant plant under ionic and osmotic stress conditions accompanied by increasing NaCl loads.
We challenged soil-grown Arabidopsis thaliana and Thellungiella salsuginea plants with short- and long-term salinity stress and monitored genome-wide gene expression and signals of guard cells that determine their function.
Arabidopsis plants suffered from both salt regimes and showed reduced stomatal conductance while Thellungiella displayed no obvious stress symptoms. The salt-dependent gene expression changes of guard cells supported the ability of the halophyte to maintain high potassium to sodium ratios and to attenuate the abscisic acid (ABA) signaling pathway which the glycophyte kept activated despite fading ABA concentrations.
Our study shows that salinity stress and even the different tolerances are manifested on a single cell level. Halophytic guard cells are less sensitive than glycophytic guard cells, providing opportunities to manipulate stomatal behavior and improve plant productivity.
Purpose
Evaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer.
Methods
338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition.
Results
Median follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%.
Conclusions
Two-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.
Many proteins are molecular machines, whose function is dependent on multiple conformational changes that are initiated and tightly controlled through biochemical stimuli. Their mechanistic understanding calls for spectroscopy that can probe simultaneously such structural coordinates. Here we present two-colour fluorescence microscopy in combination with photoinduced electron transfer (PET) probes as a method that simultaneously detects two structural coordinates in single protein molecules, one colour per coordinate. This contrasts with the commonly applied resonance energy transfer (FRET) technique that requires two colours per coordinate. We demonstrate the technique by directly and simultaneously observing three critical structural changes within the Hsp90 molecular chaperone machinery. Our results reveal synchronicity of conformational motions at remote sites during ATPase-driven closure of the Hsp90 molecular clamp, providing evidence for a cooperativity mechanism in the chaperone’s catalytic cycle. Single-molecule PET fluorescence microscopy opens up avenues in the multi-dimensional exploration of protein dynamics and allosteric mechanisms.
Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.