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Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
(2022)
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell–mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell–mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Background: The standard electrode array for the MED-EL MAESTRO cochlear implant system is 31 mm in length which allows an insertion angle of approximately 720°. When fully inserted, this long electrode array is capable of stimulating the most apical region of the cochlea. No investigation has explored Electrically Evoked Compound Action Potential (ECAP) recordings in this region with a large number of subjects using a commercially available cochlear implant system. The aim of this study is to determine if certain properties of ECAP recordings vary, depending on the stimulation site in the cochlea. Methods: Recordings of auditory nerve responses were conducted in 67 subjects to demonstrate the feasibility of ECAP recordings using the Auditory Nerve Response Telemetry (ART™) feature of the MED-EL MAESTRO system software. These recordings were then analyzed based on the site of cochlear stimulation defined as basal, middle and apical to determine if the amplitude, threshold and slope of the amplitude growth function and the refractory time differs depending on the region of stimulation. Results: Findings show significant differences in the ECAP recordings depending on the stimulation site. Comparing the apical with the basal region, on average higher amplitudes, lower thresholds and steeper slopes of the amplitude growth function have been observed. The refractory time shows an overall dependence on cochlear region; however post-hoc tests showed no significant effect between individual regions. Conclusions :Obtaining ECAP recordings is also possible in the most apical region of the cochlea. However, differences can be observed depending on the region of the cochlea stimulated. Specifically, significant higher ECAP amplitude, lower thresholds and steeper amplitude growth function slopes have been observed in the apical region. These differences could be explained by the location of the stimulating electrode with respect to the neural tissue in the cochlea, a higher density, or an increased neural survival rate of neural tissue in the apex. Trial registration: The Clinical Investigation has the Competent Authority registration number DE/CA126/AP4/3332/18/05.
Background: Simultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.
Methods/Design: This study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.
Discussion: The EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.
Trial registered at: NCT01384006
Mechanical stress is known to modulate fundamental events such as cell life and death. Mechanical stretch in particular has been identified as a positive regulator of proliferation in skin keratinocytes and other cell systems. In the present study it was investigated whether antiapoptotic signaling is also stimulated by mechanical stretch. It was demonstrated that mechanical stretch rapidly induced the phosphorylation of the proto-oncogene protein kinase B (PKB)/Akt at both phosphorylation sites (serine 473/threonine 308) in different epithelial cells (HaCaT, A-431, and human embryonic kidney-293). Blocking of phosphoinositide 3-OH kinase by selective inhibitors (LY-294002 and wortmannin) abrogated the stretch-induced PKB/Akt phosphorylation. Furthermore mechanical stretch stimulated phosphorylation of epidermal growth factor receptor (EGFR) and the formation of EGFR membrane clusters. Functional blocking of EGFR phosphorylation by either selective inhibitors (AG1478 and PD168393) or dominant-negative expression suppressed stretch-induced PKB/Akt phosphorylation. Finally, the angiotensin II type 1 receptor (AT1-R) was shown to induce positive transactivation of EGFR in response to cell stretch. These findings define a novel signaling pathway of mechanical stretch, namely the activation of PKB/Akt by transactivation of EGFR via angiotensin II type 1 receptor. Evidence is provided that stretch-induced activation of PKB/Akt protects cells against induced apoptosis.
The first measurement of two-pion Bose–Einstein correlations in central Pb–Pb collisions at √sNN=2.76 TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.
Inclusive transverse momentum spectra of primary charged particles in Pb–Pb collisions at √sNN=2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0–5% and 70–80% of the hadronic Pb–Pb cross section. The measured charged particle spectra in |η|<0.8 and 0.3<pT<20 GeV/c are compared to the expectation in pp collisions at the same sNN, scaled by the number of underlying nucleon–nucleon collisions. The comparison is expressed in terms of the nuclear modification factor RAA. The result indicates only weak medium effects (RAA≈0.7) in peripheral collisions. In central collisions, RAA reaches a minimum of about 0.14 at pT=6–7 GeV/c and increases significantly at larger pT. The measured suppression of high-pT particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb–Pb collisions at the LHC.
Rapidity and transverse momentum dependence of inclusive J/ψ production in pp collisions at √s=7 TeV
(2011)
The ALICE experiment at the LHC has studied inclusive J/ψ production at central and forward rapidities in pp collisions at √s=7 TeV. In this Letter, we report on the first results obtained detecting the J/ψ through the dilepton decay into e+e− and μ+μ− pairs in the rapidity ranges |y|<0.9 and 2.5<y<4, respectively, and with acceptance down to zero pT. In the dielectron channel the analysis was carried out on a data sample corresponding to an integrated luminosity Lint=5.6 nb−1 and the number of signal events is NJ/ψ=352±32(stat.)±28(syst.); the corresponding figures in the dimuon channel are Lint=15.6 nb−1 and NJ/ψ=1924±77(stat.)±144(syst.). The measured production cross sections are σJ/ψ(|y|<0.9)=10.7±1.0(stat.)±1.6(syst.)−2.3+1.6(syst.pol.)μb and σJ/ψ(2.5<y<4)=6.31±0.25(stat.)±0.76(syst.)−1.96+0.95(syst.pol.)μb. The differential cross sections, in transverse momentum and rapidity, of the J/ψ were also measured.
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
The ALICE experiment has measured low-mass dimuon production in pp collisions at √s=7 TeV in the dimuon rapidity region 2.5<y<4. The observed dimuon mass spectrum is described as a superposition of resonance decays (η,ρ,ω,η′,ϕ) into muons and semi-leptonic decays of charmed mesons. The measured production cross sections for ω and ϕ are σω(1<pt<5 GeV/c,2.5<y<4)=5.28±0.54(stat)±0.49(syst) mb and σϕ(1<pt<5 GeV/c,2.5<y<4)=0.940±0.084(stat)±0.076(syst) mb. The differential cross sections d2σ/dydpt are extracted as a function of pt for ω and ϕ. The ratio between the ρ and ω cross section is obtained. Results for the ϕ are compared with other measurements at the same energy and with predictions by models.
Harmonic decomposition of two particle angular correlations in Pb–Pb collisions at √sNN=2.76 TeV
(2012)
Angular correlations between unidentified charged trigger (t) and associated (a) particles are measured by the ALICE experiment in Pb–Pb collisions at √sNN=2.76 TeV for transverse momenta 0.25<pTt,a<15 GeV/c, where pTt>pTa. The shapes of the pair correlation distributions are studied in a variety of collision centrality classes between 0 and 50% of the total hadronic cross section for particles in the pseudorapidity interval |η|<1.0. Distributions in relative azimuth Δϕ≡ϕt−ϕa are analyzed for |Δη|≡|ηt−ηa|>0.8, and are referred to as “long-range correlations”. Fourier components VnΔ≡〈cos(nΔϕ)〉 are extracted from the long-range azimuthal correlation functions. If particle pairs are correlated to one another through their individual correlation to a common symmetry plane, then the pair anisotropy VnΔ(pTt,pTa) is fully described in terms of single-particle anisotropies vn(pT) as VnΔ(pTt,pTa)=vn(pTt)vn(pTa). This expectation is tested for 1⩽n⩽5 by applying a global fit of all VnΔ(pTt,pTa) to obtain the best values vn{GF}(pT). It is found that for 2⩽n⩽5, the fit agrees well with data up to pTa∼3–4 GeV/c, with a trend of increasing deviation as pTt and pTa are increased or as collisions become more peripheral. This suggests that no pair correlation harmonic can be described over the full 0.25<pT<15 GeV/c range using a single vn(pT) curve; such a description is however approximately possible for 2⩽n⩽5 when pTa<4 GeV/c. For the n=1 harmonic, however, a single v1(pT) curve is not obtained even within the reduced range pTa<4 GeV/c.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.
Kein deutscher Gegenwartsphilosoph findet weltweit eine solche Aufmerksamkeit wie Jürgen Habermas, der am 18. Juni 80 Jahre alt wird und bis zu seiner Emeritierung 1994 an der Goethe-Universität lehrte und forschte. In seiner Doppelrolle als Wissenschaftler und Intellektueller, als Gesellschaftstheoretiker und streitbarer Diskutant hat er nicht nur das Modell der diskursiven Vernunft kreiert, er ist zugleich Praktiker dieser Diskursivität und hat damit die intellektuellen Debatten der vergangenen Jahrzehnte maßgeblich beeinflusst – von der Reform der Hochschulen über Embryonenforschung bis zur Zukunft Europas.
Im Zuge der EU-Osterweiterung 2004 wurde der Gruben-Großlaufkäfer Carabus variolosus in den Anhang II der Fauna-Flora-Habitat-Richtlinie aufgenommen. Durch neu hinzugekommene Arten ergeben sich für die bisherigen Mitgliedsstaaten nach jetzigem Kenntnisstand keine Nachmeldepflichten von Gebieten, wohl aber möglicherweise die Pflicht, diese neuen Schutzobjekte in den bereits gemeldeten Gebieten gemäß Art. 6 zu erhalten und ihren günstigen Erhaltungszustand sicherzustellen (BALZER et al. 2004). Da Carabus variolosus s. str. ein osteuropäisches Taxon ist, das mitteleuropäische Taxon Carabus nodulosus aber regelmäßig als Unterart jener Art aufgefasst wird, stellt sich die Frage, ob die FFHRichtlinie mit der Nennung von C. variolosus auch das Taxon nodulosus mit gemeint hat. Der taxonomische Artbegriff ist nicht so eindeutig, dass sich die Frage auf taxonomischer Ebene nach heutigem Kenntnisstand abschließend beantworten ließe. Nach der rechtlichen Systematik der FFHRichtlinie ist aber - und dies muss zum Verständnis vorliegenden Aufsatzes hervorgehoben werden - ohnehin nicht entscheidend, wie sich der Sachverhalt nach Vorliegen weiterer Forschungen herausstellt, sondern, welche „wissenschaftliche Meinung“ zum Zeitpunkt der Meldung hierzu vorherrschte. Galt - zum Zeitpunkt der Aufnahme in den Anhang II - nodulosus in der überwiegenden wissenschaftlichen Meinung als Unterart von C. variolosus, und nicht als eigene Art, so gehören die Vorkommen in Mitteleuropa zum Anhang II, und vice versa. Aus diesem Grund handelt es sich bei der vorliegenden Arbeit auch ausdrücklich nicht um eine taxonomische. Vielmehr kann und muss anhand einer Literaturstudie - die das wissenschaftliche Meinungsbild und den Stand des Wissens widerspiegelt - versucht werden zu klären, ob Carabus (variolosus) nodulosus mit gemeint ist, wenn im erweiterten Anhang II der FFH-Richtlinie von „Carabus variolosus“ die Rede ist.
Der Schutz von Arten und ihren Lebensräumen ist sowohl mit naturschutzfachlichen Zielkonflikten, als auch mit Zielkonflikten mit anderen Bereichen wie der wirtschaftlichen Nutzung, behaftet. Forderungen nach dem besonderen Schutz von Lebensräumen und Arten sollten daher immer auf wissenschaftlicher Grundlage fußen. Neben dem Aspekt der Gefährdung, der in modernen Roten Listen zunehmend weniger gutachterlich hergeleitet wird, gewinnt das Konzept weltweiter Verantwortung an Bedeutung, und ist bei der Festlegung eines Handlungsbedarfs im Naturschutz eine wichtige Ergänzung. Laufkäfer erfüllen alle Anforderungen an eine Modellgruppe in Bezug auf die Fragestellung der Verantwortung für Lebensräume, da sie artenreich in allen terrestrischen Lebensräumen und Höhenstufen vorkommen und gut erforscht sind. Eine Auswertung der in Wäldern vorkommenden Laufkäfer Bayerns in Bezug auf Habitatbindung, Gefährdung und Verantwortung ergibt, dass es vor allem die Lebensräume auf extremen Sonderstandorten sind, die gefährdete Arten, für die wir eine besondere Schutzverantwortung haben, beheimaten. In diesen Lebensräumen müssen die Schutzanstrengungen, die auch mit den Vorgaben des §30 BNatschG (geschützte Lebensräume) und dem Anhang I der FFH-Richtlinie (und v. a. auch den prioritären Lebensraumtypen) in starkem Maße kongruent sind, in aller Konsequenz umgesetzt werden. Für die an zonale Waldtypen wie Buchen- und Eichenwälder gebundenen Arten hingegen ergibt die Analyse, dass die bestehenden Schutzbestimmungen und Schutzgebietssysteme einschließlich vorhandener Großschutzgebiete angesichts weniger gefährdeter Verantwortungsarten offenbar ausreichen. Der konsequenteste Schutz der Wälder auf Sonderstandorten mit intakten Standortsbedingungen sollte daher - zumindest gemessen an der Gruppe der Laufkäfer - höchste Aufmerksamkeit genießen.
Der Hochmoorlaufkäfer (Carabus menetriesi pacholei) ist eine prioritäre Anhang-Art der FFH-Richtlinie und Art mit hoher Schutzverantwortung Deutschlands. Seine Lebensräume liegen in noch weitgehend intakten Hoch-, Übergangs- und Hochlagen-Quellmooren einschließlich von Moorwäldern. In einem prognostizierten, wärmer und trockener werdenden Klima werden einige Vorkommen außerhalb der hier vorgelegten Klimahülle zu liegen kommen und daher für die Art voraussichtlich verloren gehen. Das gilt in besonderem Maße für die endemischen Vorkommen im Voralpengebiet. Andere Vorkommen werden nur zu halten sein, wenn jegliche Anstrengungen unternommen werden, einen naturnahen Wasserhaushalt wiederherzustellen. Die Klimahülle für die Nominatform reicht etwas weiter in den trockenen und auch warmen Bereich, erfordert aber ebenfalls sämtliche Bemühungen zu ihrem Erhalt. Zu den notwendigen Maßnahmen gehört unter anderem auch die konsequente Erhaltung naturnaher Moor- und Moorrandwälder. Eine Theorie zur Erklärung der disjunkten Verbreitung im Voralpengebiet basierend auf der Vereisungsgeschichte wird präsentiert, da die Klimaverhältnisse allein die Verbreitung nicht erklären können.
Laufkäfer werden in ökologischen Studien zur Lebensraumbewertung sehr häufig als Bioindikatoren hinzugezogen (PLATEN & KOWARIK 1995, PLATNER et al. 1996, POSPISCHIL 1981), denn ihre Ökologie und die daraus resultierenden ökologischen Ansprüche sind durch zahlreiche Studien eingehend untersucht (u.a. BAEHR 1980, LINDROTH 1945, THIELE 1977). Unterschiede in der Artengemeinschaft bzw. Änderungen in der Abundanz der Carabiden lassen Rückschlüsse über Habitatqualität, Standortsfaktoren, Minimalareal- Fragen, Habitattradition und Vernetzung von Lebensräumen zu. Diese Tatsachen wurden ausgenutzt, um die Bestandstradition und die Naturnähe der Bestockung der Probeflächen zu untersuchen. Diese sind weitgehend naturnahe Wälder im südbayerischen Tertiärhügelland, einem insgesamt wenig naturnahen, forstlich durch Fichtenforste geprägten Landschaftsraum.
Reflexive Freud-Orthodoxie
(2011)
Rezension zu: Sergio Benvenuto: Perversionen. Sexualität, Ethik und Psychoanalyse. Wien u.a.: Verlag Turia + Kant 2009. 254 Seiten, ISBN 978-3-85132-549-2, € 29,00
Abstract: Sergio Benvenuto entkoppelt die beiden Bereiche Moral und Perversion – um stattdessen ein basales Verhältnis von Ethik und Perversion zu skizzieren. Dieses diskutiert er zum einen im Rückgriff auf die freudsche Psychoanalyse. Zum anderen greift der Autor auf sozial- und moralphilosophische Erwägungen zurück. In erster Linie erweist sich der Kantische Imperativ als wegweisend für die letztlich favorisierte soziale Verhältnisbestimmung von Moral, Sexualität und Perversion.
In the absence of an active prophylactic vaccine against HIV-1, passively administered, broadly neutralizing antibodies (bnAbs) identified in some chronically infected persons were shown to prevent HIV-1 infection in animal models. However, passive administration of bnAbs may not be suited to prevent sexual HIV-1 transmission in high-risk cohorts, as a continuous high level of active bnAbs may be difficult to achieve at the primary site of sexual transmission, the human vagina with its acidic pH. Therefore, we used Lactobacillus, a natural commensal in the healthy vaginal microbiome, to express bn nanobodies (VHH) against HIV-1 that we reported previously. After demonstrating that recombinant VHHA6 expressed in E. coli was able to protect humanized mice from mucosal infection by HIV-1Bal, we expressed VHHA6 in a soluble or in a cell-wall-anchored form in Lactobacillus rhamnosus DSM14870. This strain is already clinically applied for treatment of bacterial vaginosis. Both forms of VHHA6 neutralized a set of primary epidemiologically relevant HIV-1 strains in vitro. Furthermore, VHHA6 was still active at an acidic pH. Thus, lactobacilli expressing bn VHH potentially represent an attractive vector for the passive immunization of women in cohorts at high risk of HIV-1 transmission.