Abstract
Immune checkpoint blockade using antibodies targeting the cell surface expressed proteins CTLA-4, PD-1 and PD-L1 has revolutionized cancer care and its clinical impact in several indications ...has prompted a search for complementary immunostimulatory approaches that can further increase the efficacy of these drugs. Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1; HPK1), a serine/threonine kinase expressed exclusively in hematopoietic cell lineages, mediates a negative feedback signal downstream of T-cell receptor stimulation. Its activity is enhanced by PGE2 and TGFβ, factors commonly present in the tumor microenvironment. Mice deficient for MAP4K1 or expressing a kinase-dead variant of MAP4K1 exhibit enhanced T-cell function, including increased anti-tumor immunity. We developed the small molecule inhibitor BAY-405 that displays potent nanomolar MAP4K1 inhibition in biochemical and cellular assays, good kinase selectivity, and in vivo exposure after oral dosing. Pharmacological inhibition of MAP4K1 enhances T-cell immunity and overcomes the suppressive impact of PGE2, TGFβ and CD4+ T-regulatory cells. Single agent treatment of tumor-bearing mice results in suppression of tumor outgrowth in several syngeneic models. This is accompanied by an increase in the anti-tumor T-cell response, dependent on an intact T-cell compartment, while not involving direct anti-tumor cytotoxicity. Inhibition of MAP4K1 in conjunction with PD-L1 blockade results in further suppression of tumor outgrowth. Moreover, we found that MAP4K1 is expressed in both PD-L1-high and PD-L1-low human cancers. In summary, our data show that selective inhibition of MAP4K1 by means of small molecule drugs may be used to expand the patient population responding to immune checkpoint inhibition.
Citation Format: Gabriele Leder, Rafael Carretero, Jeffrey Mowat, Sandra Berndt, Roland Neuhaus, Nuria Aiguabella Font, Ulf Boemer, Oliver von Ahsen, Uwe Eberspaecher, Judith Guenther, Mareike Grees, Corinna Link, Barbara Nicke, Daniel Baumann, Martina Schaefer, Mine Oezcan-Wahlbrink, Nicolas D. Werbeck, Ingo Hartung, Bertolt Kreft, Rienk Offringa. Enhancement of anti-tumor T-cell immunity by means of an oral small molecule targeting the intracellular immune checkpoint MAP4K1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1722.
To report a triplication of the amyloid-β precursor protein (
) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy ...(CAA) and Alzheimer disease (AD).
Four copies of the
gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization.
mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9
duplication carriers.
Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole
gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an
locus triplication, which was consistent with the presence of 2
copies in the healthy mother and with the paternal medical history. Analysis of the
mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in
duplication carriers compared with controls.
Increased copy number of
is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.
BACKGROUNDIn real-life settings, guidelines frequently cannot be followed since many patients are multimorbid and/or elderly or have other complicating conditions which carry an increased risk of ...drug-drug interactions. This document aimed to adapt recommendations from existing clinical practice guidelines (CPGs) to assist physicians' decision-making processes concerning specific and complex scenarios related to acute CAP. METHODSThe process for the adaptation procedure started with the identification of unsolved clinical questions (PICOs) in patients with CAP and continued with critically appraising the updated existing CPGs and choosing the recommendations, which are most applicable to these specific scenarios. RESULTSSeventeen CPGs were appraised to address five PICOs. Twenty-seven recommendations were endorsed based on 7 high, 9 moderate, 10 low, and 1 very low-quality evidence. The most valid recommendations applicable to the clinical practice were the following ones: Respiratory virus testing is strongly recommended during periods of increased respiratory virus activity. Assessing the severity with a validated prediction rule to discriminate where to treat the patient is strongly recommended along with reassessing the patient periodically for improvement as expected. In adults with multiple comorbidities, polypharmacy, or advanced age, it is strongly recommended to check for possible drug interactions before starting treatment. Strong graded recommendations exist on antibiotic treatment and its duration. Recommendations on the use of biomarkers such as C-reactive protein or procalcitonin to improve severity assessment are reported. CONCLUSIONThis document provides a simple and reliable updated guide for clinical decision-making in the management of complex patients with multimorbidity and CAP in the real-life setting.
The viral protein Npro is unique to the genus Pestivirus within the family Flaviviridae. After autocatalytic cleavage from the nascent polyprotein, Npro suppresses type I IFN (IFN-α/β) induction by ...mediating proteasomal degradation of IFN regulatory factor 3 (IRF-3). Previous studies found that the Npro-mediated IRF-3 degradation was dependent of a TRASH domain in the C-terminal half of Npro coordinating zinc by means of the amino acid residues C112, C134, D136 and C138. Interestingly, four classical swine fever virus (CSFV) isolates obtained from diseased pigs in Thailand in 1993 and 1998 did not suppress IFN-α/β induction despite the presence of an intact TRASH domain. Through systematic analyses, it was found that an amino acid mutation at position 40 or mutations at positions 17 and 61 in the N-terminal half of Npro of these four isolates were related to the lack of IRF-3-degrading activity. Restoring a histidine at position 40 or both a proline at position 17 and a lysine at position 61 based on the sequence of a functional Npro contributed to higher stability of the reconstructed Npro compared with the Npro from the Thai isolate. This led to enhanced interaction of Npro with IRF-3 along with its degradation by the proteasome. The results of the present study revealed that amino acid residues in the N-terminal domain of Npro are involved in the stability of Npro, in interaction of Npro with IRF-3 and subsequent degradation of IRF-3, leading to downregulation of IFN-α/β production.
Membrane transporters play a central role in many cellular processes that rely on the movement of ions and organic molecules between the environment and the cell, and between cellular compartments. ...Transporters have been well characterized in plants and green algae, but little is known about transporters or their evolutionary histories in the red algae. Here we examined 482 expressed sequence tag contigs that encode putative membrane transporters in the economically important red seaweed Porphyra (Bangiophyceae, Rhodophyta). These contigs are part of a comprehensive transcriptome dataset from Porphyra utnbilicalis and Porphyra purpurea. Using phylogenomics, we identified 30 trees that support the expected monophyly of red and green algae/plants (i.e. the Plantae hypothesis) and 19 expressed sequence tag contigs that show evidence of endosymbiotic/horizontal gene transfer involving stramenopiles. The majority (77%) of analyzed contigs encode transporters with unresolved phylogenies, demonstrating the difficulty in resolving the evolutionary history of genes. We observed molecular features of many sodium-coupled transport systems in marine algae, and the potential for coregulation of Porphyra transporter genes that are associated with fatty acid biosynthesis and intracellular lipid trafficking. Although both the tissue-specific and subcellular locations of the encoded proteins require further investigation, our study provides red algal gene candidates associated with transport functions and novel insights into the biology and evolution of these transporters.
The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes ...and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P(heterogeneity) = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
Probing of Hermean exosphere by ultraviolet spectroscopy (PHEBUS) is a double spectrometer for the Extreme Ultraviolet range (55–155
nm) and the Far Ultraviolet range (145–315
nm) devoted to the ...characterization of Mercury's exosphere composition and dynamics, and surface–exosphere connections. This French-led instrument is implemented in a cooperative scheme involving Japan (detectors), Russia (scanner) and Italy (ground calibration). PHEBUS will address the following main scientific objectives relative to Mercury's exosphere: determination of the composition and the vertical structure of the exosphere; characterization of the exospheric dynamics: day to night circulation, transport between active and inactive regions; study of surface release processes; identification and characterization of the sources of exospheric constituents; detection and characterization of ionized species and their relation with the neutral atmosphere; space and time monitoring of exosphere/magnetosphere exchange and transport processes; study and quantification of escape, global scale source/sink balance and geochemical cycles synergistically with other experiments of BepiColombo (Mercury Sodium Atmospheric Spectral Imager (MSASI), Mercury Plasma Particle Experiment (MPPE) on Mercury Magnetospheric Orbiter (MMO); Mercury imaging X-ray spectrometer (MIXS), Search for exosphere refilling and emitted neutral abundance (SERENA) on Mercury Planetary Orbiter (MPO)). Two gratings and two detectors are used according to a specific, compact design. The spectrum detection is based on the photon counting method and is realized using micro-channel plate (MCP) detectors with Resistive Anode Encoder (RAE). Typical photocathodes are CsI or KBr for the extreme ultra-violet (EUV) range, CsTe for the far ultra-violet (FUV) range. Extra visible lines are monitored using a photo-multiplier (PM) that is also used in photon counting mode. In order to prevent sensitivity losses which are critical in UV ranges, a minimum of reflections is achieved inside the instrument using only an off-axis parabola and a set of holographic gratings. A one degree-of-freedom scanning system allows to probe, at the highest possible signal-to-noise ratio, selected regions and altitude ranges of interest. Different modes of observation will be used sequentially (vertical scans, along-orbit scans, grazing observations at twilight, etc.). During the mission, the instrument will be regularly calibrated on well chosen stars, in such a way to quantitatively estimate the overall degradation of the sensitivity of the instrument.
BepiColombo, a mission of ESA (European Space Agency) in cooperation with JAXA (Japan Aerospace Exploration Agency), will explore Mercury, the planet closest to the Sun. BepiColombo will launch in ...2014 on a journey lasting up to six and a half years; the data gathering phase should occupy a one year nominal mission, with a possible extension of another year. The data which will be brought back from the orbiters will tell us about the Hermean surface, atmospheric composition, and magnetospheric dynamics; it will also contribute to understanding the history and formation of terrestrial planets. The PHEBUS (Probing of Hermean Exosphere by Ultraviolet Spectroscopy) instrument will be flown on MPO: Mercury Planetary Orbiter, one of the two BepiColombo orbiters. The main purpose of the instrument is to reveal the composition and the distribution of the exosphere of Mercury through EUV (Extreme Ultraviolet: 55–155nm) and FUV (Far Ultraviolet: 145–315nm) measurements. A consortium composed of four main countries has been formed to build it. Japan provides the two detectors (EUV and FUV), Russia implements the scanning system, and France and Italy take charge of the overall design, assembly, test, integration, and also provide two small NUV (Near Ultraviolet) detectors (for the light from calcium and potassium molecules). An optical prototype of the EUV detector which is identical to the flight configuration has been manufactured and evaluated. In this paper, we show the first spectra results observed by the EUV channel optical prototype. We also describe the design of PHEBUS and discuss the possibility of detecting noble gases in Mercury’s exosphere taking the experimental results so far into account.
Coral reef preservation is a challenge for the whole of humanity, not just for the estimated three billion people that directly depend upon coral reefs for their livelihoods and food security. Ocean ...acidification combined with rising sea surface temperatures, and an array of other anthropogenic influences such as pollution, sedimentation, over fishing, and coral mining represent the key threats currently facing coral reef survival. Here we summarize a list of agreements, policies, and socio-economic tools and instruments that can be used by global, national and local decision-makers to address ocean acidification and associated threats, as identified during an expert workshop in October 2017. We then discuss these tools and instruments at a global level and identify the key tasks for raising decision makers’ awareness. Finally, we suggest ways of prioritizing between different actions or tools for mitigation and adaptation.
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