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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.
Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells. Macrophage activation was impaired when glycolysis was blocked by chemical inhibitors. Remarkably, lactate was found to inhibit LPS-induced glycolysis in wild type as well as in Gpr81-/- cells. In conclusion, our study suggests that lactate can induce GPR81-independent metabolic changes that modulate macrophage pro-inflammatory activation.
Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive.
Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging.
Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation.
Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.
Objectives: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE).
Materials and methods: Exploratory post hoc analyses of a double‐blind, initial monotherapy trial of lacosamide vs carbamazepine‐controlled release (carbamazepine‐CR) (SP0993; NCT01243177); a double‐blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline.
Results: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine‐CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine‐CR) reported treatment‐emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine‐CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine‐CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure‐free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure‐free.
Conclusions: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine‐CR.
Lack of efficacy of a partial adenosine A1 receptor agonist in neuropathic pain models in mice
(2021)
Previous studies suggest that adenosine A1 receptors (A1R) modulate the processing of pain. The aim of this study was to characterize the distribution of A1R in nociceptive tissues and to evaluate whether targeting A1R with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of A1R in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found A1R to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03–1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full A1R agonist. Despite expression of A1R in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial A1R agonists might be a valuable approach for the treatment of neuropathic pain.
Objectives: Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Methods: Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for the treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. Results: DRV showed no antiviral activity against SARS-CoV-2 at clinically relevant concentrations (EC50 > 100 μM). Remdesivir, used as a positive control, demonstrated potent antiviral activity (EC50 = 0.38 μM). Conclusions: Overall, the data do not support the use of DRV for the treatment of COVID-19.
Literatur ist mehr als eine Belegstelle für literatur- oder medientheoretische Thesen, anderseits erschließt sie sich nicht selbst, sondern antwortet auf Bezugsprobleme. Das Problem, das ich mit Blick auf "Schrift" an Heinrich Heine herantragen möchte, ist die Frage, ob die Literatur sich selbst als Medium beobachtet und ob mit der Figur des 'Jehuda ben Halevy' womöglich Autorschaft unter Bedingungen konkurrierender Medien reflektiert wird. Meine medienkomparatistische Lektüre zielt auf jene Medien der Literatur, die Heine im 'Romanzero' thematisiert und als Bedingung seines eigenen Schreibens reflektiert. Ausgehend von dieser vergleichenden Analyse der Medien des 'Romanzero' werde ich in einem zweiten Teil die hinzugezogenen Medientheorien daraufhin befragen, welche Fragen sie an die Literatur herantragen und welche Antworten sie auf Probleme literarischer Texte geben können.
Es sind literarische Texte, die das Corpus des folgenden Beitrages ausmachen. Die Fragen, die an diese Texte gestellt werden, sind indes sozialgeschichtlicher Natur: Über welche sozialen Gruppen wird gelacht? Welche Haltung wird durch die Komik zum Ausdruck gebracht? Wird durch das Lachen die bestehende soziale Ordnung bestätigt oder in Frage gestellt? Diese drei Fragen sollen für den Bereich der französischen Literatur in drei Schritten untersucht werden: zunächst soll nach der Funktion der Komik im Ancien Régime im Zusammenhang mit dem hierarchischen Gattungssystem, das mit der sozialen Hierarchie in Verbindung steht, gefragt werden; danach gilt es, die Funktion der Komik nach der Französischen Revolution mit dem Einbruch des Gattungs- und Sozialsystems zu untersuchen; ein letzter Abschnitt gilt der Wiederentdeckung Rabelais’ durch die romantische Generation mit ihrer Neueinschätzung des Komischen.
Die Tatsache, dass die Verbindung der phantastischen Literatur und des Lachens in der deutschsprachigen Literatur einen wichtigen Stellenwert besitzt, belegen manche Werke der eruierten Autoren der phantastischen Literatur wie Gustav Meyrink, Alfred Kubin, Hans Heinz Ewers, Karl Hans Strobl oder Hans Watzlik. So ist diese eigenartige Mischung z.B. für das Frühwerk Gustav Meyrinks kennzeichnend. Seine frühe Kurzprosa hebt sich von seinen späteren Romanen v. a. durch die Neigung zum Humor und zur Ironie ab. Die Eigenart der frühen Erzählungen, die in den Bänden „Der heiße Soldat und andere Geschichten“ (1903), „Das Wachsfigurenkabinett“ (1907) und „Des deutschen Spießers Wunderhorn“ (1913) erschienen, beruht infolgedessen auf der Verschmelzung der Gattung der Schauergeschichte oder der okkultistischen Geschichte und des Humors.