Although T cells can develop into an exhausted state in the tumour microenvironment, tumour infiltrating T cells (TILs) are important to control tumour growth. By analysing single cell RNA-sequencing ...data from human tumours, we found that the transcription factors Early Growth Response 2 (EGR2) and 3 were highly induced in TILs, but not peripheral CD8 + T cells, in multiple patient cohorts. We found that deficiency of Egr2 and 3 in T cells resulted in enhanced tumour growth and fewer TILs in mouse models. Egr2 is highly expressed together with checkpoint molecules in a proportion of CD8 + TILs and Egr2high cells exhibit better survival and proliferation than Egr2
-/-
Egr3
-/-
and Egr2low TILs. Anti-PD-1 treatment increases Egr2 expression in CD8 + TILs and reduces tumour growth, while anti-PD-1 efficacy is abrogated in the absence of Egr2 and 3. Thus, Egr2 and 3 are important for maintaining anti-tumour responses of exhausted CD8 + TILs.
Perampanel Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ...receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.
Periodontitis as a comorbidity in systemic lupus erythematosus (SLE) is still not well recognized in the dental and rheumatology communities. A meta-analysis and network meta-analysis were thus ...performed to compare the (i) prevalence of periodontitis in SLE patients compared to those with rheumatoid arthritis (RA) and (ii) odds of developing periodontitis in controls, RA, and SLE.
Pooled prevalence of and odds ratio (OR) for periodontitis were compared using meta-analysis and network meta-analysis (NMA).
Forty-three observational studies involving 7,800 SLE patients, 49,388 RA patients, and 766,323 controls were included in this meta-analysis. The pooled prevalence of periodontitis in SLE patients (67.0%, 95% confidence interval CI 57.0-77.0%) was comparable to that of RA (65%, 95% CI 55.0-75.0%) (p>0.05). Compared to controls, patients with SLE (OR=2.64, 95% CI 1.24-5.62, p<0.01) and RA (OR=1.81, 95% CI 1.25-2.64, p<0.01) were more likely to have periodontitis. Indirect comparisons through the NMA demonstrated that the odds of having periodontitis in SLE was 1.49 times higher compared to RA (OR=1.49, 95% CI 1.09-2.05, p<0.05).
Given that RA is the autoimmune disease classically associated with periodontal disease, the higher odds of having periodontitis in SLE are striking. These results highlight the importance of addressing the dental health needs of patients with SLE.
https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021272876.
Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and ...differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ, providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology.
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone ...targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
T-bet is important for differentiation of cytotoxic CD8 and Th1 CD4 T cells. We have discovered that Egr2 and 3 are potent inhibitors of T-bet function in CD4 and CD8 effector T cells. Egr2 and 3 ...were essential to suppress Th1 differentiation in Th2 and Th17 conditions in vitro and also to control IFN-γ-producing CD4 and CD8 T cells in response to virus infection. Together with Egr2 and 3, T-bet is induced in naive T cells by Ag stimulation, but Egr2 and 3 expression was inhibited by Th1-inducing cytokines. We found that Egr2 and 3 physically interact with the T-box domain of T-bet, blocking T-bet DNA binding and inhibiting T-bet-mediated production of IFN-γ. Thus, Egr2 and 3 are antagonists of T-bet function in effector T cells and are important for the control of inflammatory responses of T cells.
Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases
generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic
peptides Aβ40 and Aβ42-the major constituents of ...the amyloid
plaques in the brain parenchyma of Alzheimer's disease patients.
There is evidence that the polytopic membrane-spanning proteins, presenilin
1 and 2 (PS1 and PS2), are important determinants of γ-secretase activity:
mutations in PS1 and PS2 that are associated with early-onset familial
Alzheimer's disease increase the production of Aβ42
(refs 4,5,6), the more amyloidogenic peptide; γ-secretase activity
is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane
segments of PS1 inactivates the ability of γ-secretase to catalyse processing
of APP within its transmembrane domain. It is unknown, however,
whether PS1 (which has little or no homology to any known aspartyl protease)
is itself a transmembrane aspartyl protease or a γ-secretase cofactor,
or helps to colocalize γ-secretase and APP. Here we report photoaffinity
labelling of PS1 (and PS2) by potent γ-secretase inhibitors that were
designed to function as transition state analogue inhibitors directed to the
active site of an aspartyl protease. This observation indicates that PS1 (and
PS2) may contain the active site of γ-secretase. Interestingly, the
intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed
photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl
protease zymogen.
Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the ...effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event.
We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina.
The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval CI, 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo.
In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.).
A narrow structure in the pΛover ¯ system near the mass threshold, named as X(2085), is observed in the process e^{+}e^{-}→pK^{-}Λover ¯ with a statistical significance greater than 20σ. Its spin and ...parity are determined for the first time to be J^{P}=1^{+} in an amplitude analysis, with a statistical significance greater than 5σ over other quantum numbers (0^{-},1^{-} and 2^{+}). The pole positions of X(2085) are measured to be M_{pole}=(2084_{-2}^{+4}±9) MeV and Γ_{pole}=(58_{-3}^{+4}±25) MeV, where the first uncertainties are statistical and the second ones are systematic. The analysis is based on the study of the process e^{+}e^{-}→pK^{-}Λover ¯ and uses the data samples collected with the BESIII detector at the center-of-mass energies sqrts=4.008, 4.178, 4.226, 4.258, 4.416, and 4.682 GeV with a total integrated luminosity of 8.35 fb^{-1}.
We report the measurement of the inclusive cross sections for e^{+}e^{-}→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to ...3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I set II, the R(3810) state has mass (3805.7±1.1±2.7) (3805.7±1.1±2.7) MeV/c^{2}, total width (11.6±2.9±1.9) (11.5±2.8±1.9) MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) (11.0±3.4±2.5) eV. In addition, we measure the branching fractions BR(3760)→nOCH=(25.2±16.1±30.4)%(6.4±4.8±7.7)% and BR(3780)→nOCH=(12.3±6.6±8.3)%(10.4±4.8±7.0)% for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.
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