Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis.

CD8+ T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+ T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+ T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+ T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+ T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+ T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+ T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+ T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+ CD8+ T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+ T cells in MS, indicates these cells may be attractive targets in MS therapy

Increased TCR Avidity after T Cell Activation A Mechanism for Sensing Low-Density Antigen

AbstractWhile activated T cells are known to have enhanced biological responses to antigen stimulation, the biophysical basis of this increased sensitivity remains unknown. Here, we show that, on activated T cells, the TCR avidity for peptide-MHC complexes is 20- to 50-fold higher than the TCR avidity of naive T cells. This increased avidity for peptide-MHC depends on TCR reorganization and is sensitive to the cholesterol content of the T cell membrane. Analysis of the binding data indicates the enhanced avidity is due to increases in cross-linking of TCR on activated T cells. Activation-induced membrane (AIM) changes in TCR avidity represent a previously unrecognized means of increasing the sensitivity of activated T cells to small amounts of antigen in the periphery

Drawing Shortest Paths in Geodetic Graphs

Motivated by the fact that in a space where shortest paths are unique, no two shortest paths meet twice, we study a question posed by Greg Bodwin: Given a geodetic graph $G$, i.e., an unweighted graph in which the shortest path between any pair of vertices is unique, is there a philogeodetic drawing of $G$, i.e., a drawing of $G$ in which the curves of any two shortest paths meet at most once? We answer this question in the negative by showing the existence of geodetic graphs that require some pair of shortest paths to cross at least four times. The bound on the number of crossings is tight for the class of graphs we construct. Furthermore, we exhibit geodetic graphs of diameter two that do not admit a philogeodetic drawing.Comment: Appears in the Proceedings of the 28th International Symposium on Graph Drawing and Network Visualization (GD 2020

Studying the Potential of Multi-Target Classification to Characterize Combinations of Classes with Skewed Distribution

The identification of subpopulations with particu-lar characteristics with respect to a disease is important for personalized diagnostics and therapy design. For some diseases, the outcome is described by more than one target variable. An example is tinnitus: the perceived loudness of the phantom signal and the level of distress caused by it are both relevant targets for diagnosis and therapy. In this work, we study the potential of multi-target classification for the identification of those screening variables, which separate best among the different subpopula-tions of patients, paying particular attention to subpopulations with discordant value combinations of loudness and distress. We analyse the screening data of 1344 tinnitus patients from the University Hospital Regensburg, including questions from 7 questionnaires, and report on the performance of our workflow in target separation and in ranking the questionnaires’ variables on their discriminative power

Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome

Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases

Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf–Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. Here, a combination of kinetic isotope effect measurements and quantum chemical modeling was used to provide subangstrom details of the transition state structure for NSD2 enzymatic activity. Kinetic isotope effects were measured for the methylation of isolated HeLa cell nucleosomes by NSD2. NSD2 preferentially catalyzes the dimethylation of H3K36 along with a reduced preference for H3K36 monomethylation. Primary Me-(14)C and (36)S and secondary Me-(3)H(3), Me-(2)H(3), 5′-(14)C, and 5′-(3)H(2) kinetic isotope effects were measured for the methylation of H3K36 using specifically labeled S-adenosyl-l-methionine. The intrinsic kinetic isotope effects were used as boundary constraints for quantum mechanical calculations for the NSD2 transition state. The experimental and calculated kinetic isotope effects are consistent with an S(N)2 chemical mechanism with methyl transfer as the first irreversible chemical step in the reaction mechanism. The transition state is a late, asymmetric nucleophilic displacement with bond separation from the leaving group at (2.53 Å) and bond making to the attacking nucleophile (2.10 Å) advanced at the transition state. The transition state structure can be represented in a molecular electrostatic potential map to guide the design of inhibitors that mimic the transition state geometry and charge

Nucleated red blood cells are a late biomarker in predicting intensive care unit mortality in patients with COVID-19 acute respiratory distress syndrome: an observational cohort study

BackgroundNucleated red blood cells (nRBC) are precursor cells of the erythropoiesis that are absent from the peripheral blood under physiological conditions. Their presence is associated with adverse outcomes in critically ill patients. This study aimed to evaluate the predictive value of nRBC on mortality in intensive care unit (ICU) patients with COVID-19 acute respiratory distress syndrome (ARDS).Material and methodsThis retrospective, observational cohort study analyzed data on 206 ICU patients diagnosed with COVID-19 ARDS between March 2020 and March 2022. The primary endpoint was ICU mortality, and secondary endpoints included ICU and hospital stay lengths, ventilation hours, and the time courses of disease severity scores and clinical and laboratory parameters.ResultsAmong the included patients, 68.9% tested positive for nRBC at least once during their ICU stay. A maximum nRBC of 105 µl-1 had the highest accuracy in predicting ICU mortality (area under the curve of the receiver operating characteristic [AUCROC] 0.780, p < 0.001, sensitivity 69.0%, specificity 75.5%). Mortality was significantly higher among patients with nRBC >105 µl-1 than ≤105 µl-1 (86.5% vs. 51.3%, p = 0.008). Compared to patients negative for nRBC in their peripheral blood, those positive for nRBC required longer mechanical ventilation (127 [44 - 289] h vs. 517 [255 - 950] h, p < 0.001), ICU stays (12 [8 – 19] vs. 27 [13 – 51] d, p < 0.001), and hospital stays (19 [12 - 29] d vs. 31 [16 - 58] d, p < 0.001). Peak Sepsis-related Organ Failure Assessment (SOFA), Simplified Acute Physiology Score, PaO2/FiO2, interleukin-6, and procalcitonin values were reached before the peak nRBC level. However, the predictive performance of the SOFA (AUCROC 0.842, p < 0.001) was considerably improved when a maximum SOFA score >8 and nRBC >105 µl-1 were combined.DiscussionnRBC predict ICU mortality and indicate disease severity among patients with COVID-19 ARDS, and they should be considered a clinical alarm signal for a worse outcome. nRBC are a late predictor of ICU mortality compared to other established clinical scoring systems and laboratory parameters but improve the prediction accuracy when combined with the SOFA score

Distinct nonequilibrium plasma chemistry of C2 affecting the synthesis of nanodiamond thin films from C2H2 (1%)/H2/Ar-rich plasmas

6 pages, 5 figures, 6 tables.We show that the concentrations of the species C2 (X 1Σg+), C2 (a 3Πu), and C2H exhibit a significant increase when the argon content grows up to 95% in medium pressure (0.75 Torr) radio frequency (rf) (13.56 MHz) produced C2H2 (1%)/H2/Ar plasmas of interest for the synthesis of nanodiamond thin films within plasma enhanced chemical vapor deposition devices. In contrast, the concentrations of CH3 and C2H2 remain practically constant. The latter results have been obtained with an improved quasianalytic space–time-averaged kinetic model that, in addition, has allowed us to identify and quantify the relative importance of the different underlying mechanisms driving the nonequilibrium plasma chemistry of C2. The results presented here are in agreement with recent experimental results from rf CH4/H2/Ar-rich plasmas and suggest that the growth of nanodiamond thin films from hydrocarbon/Ar-rich plasmas is very sensitive to the contribution of C2 and C2H species from the plasma.This work was partially funded by CICYT (Spain) under a Ramón y Cajal project and under Project No. TIC2002- 03235. One of the authors (F.J.G.V.) acknowledges a Ramón y Cajal contract from the Spanish Ministry of Science and Technology (MCYT). One of the authors (J.M.A.) acknowledges partial support from CICYT (Spain) under Project No. MAT 2002-04085-C02-02.Peer reviewe