Stereoselective Total Synthesis of (−)‐Thallusin for Bioactivity Profiling

Chemical mediators are key compounds for controlling symbiotic interactions in the environment. Here, we disclose a fully stereoselective total synthesis of the algae differentiation factor (−)‐thallusin that utilizes sophisticated 6‐ endo ‐cyclization chemistry and effective late‐stage sp 2 –sp 2 ‐couplings using non‐toxic reagents. An EC 50 of 4.8 pM was determined by quantitative phenotype profiling in the green seaweed Ulva mutabilis (Chlorophyte), underscoring this potent mediator‘s enormous, pan‐species bioactivity produced by symbiotic bacteria. SAR investigations indicate that (−)‐thallusin triggers at least two different pathways in Ulva that may be separated by chemical editing of the mediator compound structure

Therapy preferences of patients with lung and colon cancer: A discrete choice experiment

Objectives: There is increasing interest in studies that examine patient preferences to measure health-related outcomes. Understanding patients’ preferences can improve the treatment process and is particularly relevant for oncology. In this study, we aimed to identify the subgroup-specific treatment preferences of German patients with lung cancer (LC) or colorectal cancer (CRC). Methods: Six discrete choice experiment (DCE) attributes were established on the basis of a systematic literature review and qualitative interviews. The DCE analyses comprised generalized linear mixed-effects model and latent class mixed logit model. Results: The study cohort comprised 310 patients (194 with LC, 108 with CRC, 8 with both types of cancer) with a median age of 63 (SD =10.66) years. The generalized linear mixed-effects model showed a significant (P<0.05) degree of association for all of the tested attributes. “Strongly increased life expectancy” was the attribute given the greatest weight by all patient groups. Using latent class mixed logit model analysis, we identified three classes of patients. Patients who were better informed tended to prefer a more balanced relationship between length and health-related quality of life (HRQoL) than those who were less informed. Class 2 (LC patients with low HRQoL who had undergone surgery) gave a very strong weighting to increased length of life. We deduced from Class 3 patients that those with a relatively good life expectancy (CRC compared with LC) gave a greater weight to moderate effects on HRQoL than to a longer life. Conclusion: Overall survival was the most important attribute of therapy for patients with LC or CRC. Differences in treatment preferences between subgroups should be considered in regard to treatment and development of guidelines. Patients’ preferences were not affected by sex or age, but were affected by the cancer type, HRQoL, surgery status, and the main source of information on the disease

Characterization of an Aldehyde Oxidoreductase From the Mesophilic Bacterium Aromatoleum aromaticum EbN1, a Member of a New Subfamily of Tungsten-Containing Enzymes

The biochemical properties of a new tungsten-containing aldehyde oxidoreductase from the mesophilic betaproteobacterium Aromatoleum aromaticum EbN1 (AORAa) are presented in this study. The enzyme was purified from phenylalanine-grown cells of an overexpressing mutant lacking the gene for an aldehyde dehydrogenase normally involved in anaerobic phenylalanine degradation. AORAa catalyzes the oxidation of a broad variety of aldehydes to the respective acids with either viologen dyes or NAD+ as electron acceptors. In contrast to previously known AORs, AORAa is a heterohexameric protein consisting of three different subunits, a large subunit containing the W-cofactor and an Fe-S cluster, a small subunit containing four Fe-S clusters, and a medium subunit containing an FAD cofactor. The presence of the expected cofactors have been confirmed by elemental analysis and spectrophotometric methods. AORAa has a pH optimum of 8.0, a temperature optimum of 40°C and is completely inactive at 50°C. Compared to archaeal AORs, AORAa is remarkably resistant against exposure to air, exhibiting a half-life time of 1 h as purified enzyme and being completely unaffected in cell extracts. Kinetic parameters of AORAa have been obtained for the oxidation of one aliphatic and two aromatic aldehydes, resulting in about twofold higher kcat values with benzyl viologen than with NAD+ as electron acceptor. Finally, we obtained evidence that AORAa is also catalyzing the reverse reaction, reduction of benzoate to benzaldehyde, albeit at very low rates and under conditions strongly favoring acid reduction, e.g., low pH and using Ti(III) citrate as electron donor of very low redox potential. AORAa appears to be a prototype of a new subfamily of bacterial AOR-like tungsten-enzymes, which differ from the previously known archaeal AORs mostly by their multi-subunit composition, their low sensitivity against oxygen, and the ability to use NAD+ as electron acceptor

Stereoselektive Totalsynthese von (−)‐Thallusin zur Bioaktivitätsprofilierung

Chemische Mediatoren sind Schlüsselverbindungen zur Kontrolle von Symbiosen in unserer Umwelt. Hier berichten wir über eine völlig stereoselektive Totalsynthese des Algendifferenzierungsfaktors (−)‐Thallusin, die sich durchdachter 6‐ endo ‐Zyklisierungschemie und effektiver sp 2 –sp 2 ‐Kupplungen mittels Zinn‐freier Reagenzien auf späten Stufen bedient. Durch quantitative phänotypische Profilierung wurde für die weit verbreitete Grünalge Ulva mutabilis (Chlorophyta) ein EC 50 ‐Wert von 4.8 pM ermittelt, was die enorme artenübergreifende Bioaktivität dieses von symbiotischen Bakterien produzierten Mediators aufzeigt. SAR‐Untersuchungen weisen darauf hin, dass (−)‐Thallusin mindestens zwei unterschiedliche Signalwege in Ulva auslöst, die durch chemische Editierung der Mediatorstruktur separiert werden können

Cervical Artery Dissection in Young Adults in the Stroke in Young Fabry Patients (sifap1) Study

Background: Patients with carotid artery dissection (CAD) have been reported to have different vascular risk factor profiles and clinical outcomes to those with vertebral artery dissection (VAD). However, there are limited data from recent, large international studies comparing risk factors and clinical features in patients with cervical artery dissection (CeAD) with other TIA or ischemic stroke (IS) patients of similar age and sex. Methods: We analysed demographic, clinical and risk factor profiles in TIA and IS patients ≤55 years of age with and without CeAD in the large European, multi-centre, Stroke In young FAbry Patients 1 (sifap1) study. Patients were further categorised according to age (younger: 18-44 years; middle-aged: 45-55 years), sex, and site of dissection. Results: Data on the presence of dissection were available in 4,208 TIA and IS patients of whom 439 (10.4%) had CeAD: 196 (50.1%) had CAD, 195 (49.9%) had VAD, and 48 had multiple artery dissections or no information regarding the dissected artery. The prevalence of CAD was higher in women than in men (5.9 vs. 3.8%, p < 0.01), whereas the prevalence of VAD was similar in women and men (4.6 vs. 4.7%, n.s.). Patients with VAD were younger than patients with CAD (median = 41 years (IQR = 35-47 years) versus median = 45 years (IQR = 39-49 years); p < 0.01). At stroke onset, about twice as many patients with either CAD (54.0 vs. 23.1%, p < 0.001) or VAD (63.4 vs. 36.6%, p < 0.001) had headache than patients without CeAD and stroke in the anterior or posterior circulation, respectively. Compared to patients without CeAD, hypertension, concomitant cardiovascular diseases and a patent foramen ovale were significantly less prevalent in both CAD and VAD patients, whereas tobacco smoking, physical inactivity, obesity and a family history of cerebrovascular diseases were found less frequently in CAD patients, but not in VAD patients. A history of migraine was observed at a similar frequency in patients with CAD (31%), VAD (27.8%) and in those without CeAD (25.8%). Conclusions: We identified clinical features and risk factor profiles that are specific to young patients with CeAD, and to subgroups with either CAD or VAD compared to patients without CeAD. Therefore, our data support the concept that certain vascular risk factors differentially affect the risk of CAD and VAD

Beiträge zur Geschichte des Landkreises Regensburg 6

Das Donautal zwischen Regensburg und Wörth - Beschreibungen und Bilder aus fünf Jahrhunderten; darin: Fendl, Josef: Kaufmannszüge, Treidelpferde und Ordinarischiffe / Zur Verkehrsgeschichte des Regensburger Südostens (S. 3); Arndt, Ernst Moritz: Dem Mäandrischen Strome nach (S. 9); Zur Beruhigung der Reisenden (S. 9); Weber, Carl Julius: Die Nymphen der Donau (S. 9); Bundschue, Johann: So gut wie im Wirtshause (S. 10); Schultes, Joseph August: Herrliche Landschaftsstücke (S. 10); Schultes, Joseph August: Eine sonderbare Erscheinung (S. 10); Schindler, Herbert, Ein Bau aus dem Tagen Barbarossas (S. 11); Schindler, Herbert: Ein Treffpunkt der Romantiker (S. 12); Schindler, Herbert: Dieses lyrische Land (S. 13); Dielhelm, Johann Hermann: Auf einem ziemlich hohen Berg (S. 13); Bepanzert bis zum Scheitel (S. 14); Schultes, Joseph August: Eine der schönsten Punkte (S. 14); Dem Deutschen Ruhme (S. 16); Fürst von Metternich, Clemens: Ein Wald von abgeschnittenen Köpfen (S. 17); Donner, Jos. Alex.: Unheimlich aussehende Donaustaufer (S. 17); Fendl, Josef: Eine verzauberte romantische Landschaft (S. 18); Schultes, Joseph August: In mineralogischer Hinsicht merkwürdig (S. 20); Schultes, Joseph August: Ein Jägersteig am Scheuchen (S. 20); Schultes, Joseph August: Der gefürchtete Baierwein (S. 21); Schultes, Joseph August: Unbedeutende alte Dörfer (S. 22); Ein stattliches Kirchdorf (S. 22); Kaiser Joseph II.: Eine Messe auf dem Donauufer (S. 23); Schindler, Herbert: Wie ein Wachauer Weindorf (S. 23); J.H.: Die Donau bei Wiesent (S. 24); Schultes, Joseph August: Eine Art von Tantalischer Fahrt (S. 24); Der Wein hat viel Schneide (S. 25); Roedig, Michael: Spiegelwellen nach Deutscher Art (S. 25); Roedig, Michael: Etwas von süßer Wehmuth (S. 26); Arndt, Ernst Moritz: Wir landeten im Dorfe Pater (S. 26); Dielhelm, Johann Hermann: Ein feiner Marktflecken (S. 26); Schultes, Joseph August: Ein alter römischer Waffenplatz (S. 28); Berühmt durch die Bayerischen Rüben (S. 28); Fendl, Josef: St. Nikola in Pfatter (S. 28); Schultes, Joseph August: Das schöne, uralte Wörth (S. 29); Eine glückliche Lage (S. 29); Dunzinger, Franz Xaver: Die hehrste der Burgen (S. 30); Schindler, Herbert: Herbes Mittelalter und heitere Renaissance (S. 31); Freyberger, Laurentius: Magie der Donaulandschaft (S. 31); Bauer, Josef Martin: Ein Strom im Strom (S. 33); Britting, Georg: Wie ein silberner Fisch (S. 33

Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy