Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC’s systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.publishedVersio

Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology

International audienceThe first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.Significance Statement⎯MMPs have been implicated in most inflammatory, autoimmune, cancers and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases

Available phosphorus in diets for 15 to 30 kg pigs genetically selected for meat deposition

With the objective to evaluate the effect of dietary available phosphorus levels (aP) on the performance, blood and bone parameters of castrated male and female pigs, genetically selected for meat deposition, 60 commercial hybrids pigs with initial weight of 15.54±0.68 kg were allotted in a completely randomized block design, with six treatments (0.103, 0.210, 0.317, 0.424, 0.531, and 0.638% aP), five replicates, and two animals per experimental unit. Pigs were fed ad libitum and water was provided until the end of the experimental period (21 days), when animals reached 31.31±2.94 kg. Daily weight gain and daily feed intake increased, while the feed conversion improved quadratically up to 0.534, 0.487, and 0.574% aP maximum responses, respectively. The aP intake and the values of inorganic phosphorus in serum increased linearly with increasing the levels of aP in the diets. Alkaline phosphatase activity increased quadratically up to 0.558% maximum response. Bone breaking strength and calcium, phosphorus, and ash contents in the bones increased linearly with increasing aP concentration in the diets. The available phosphorus requirement of castrated male and female pigs genetically selected for meat deposition from 15 to 30 kg for best results of performance is 0.574%, corresponding to a daily intake of 8.26 g of available phosphorus

Measurement of Ξc+\Xi_{c}^{+} production in ppPb collisions at sNN=8.16\sqrt{s_{NN}}=8.16 TeV at LHCb

International audienceA study of prompt $\Xi_{c}^{+}$ production in proton-lead collisions is performed with the LHCb experiment at a centre-of-mass energy per nucleon pair of 8.16 TeV in 2016 in $p$Pb and Pb$p$ collisions with an estimated integrated luminosity of approximately 12.5 and 17.4 nb$^{-1}$, respectively. The $\Xi_{c}^{+}$ production cross-section, as well as the $\Xi_{c}^{+}$ to $\Lambda_{c}^{+}$ production cross-section ratio, are measured as a function of the transverse momentum and rapidity and compared to latest theory predictions. The forward-backward asymmetry is also measured as a function of the $\Xi_{c}^{+}$ transverse momentum

A study of C ⁣PC\!P violation in the decays B±→[K+K−π+π−]Dh±B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm} (h=K,πh = K, \pi) and B±→[π+π−π+π−]Dh±B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^{\pm}

The first study of $C\!P$ violation in the decay mode $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm}$, with $h=K,\pi$, is presented, exploiting a data sample of proton-proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9$ fb$^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm}$ and $B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^{\pm}$ decays.The first study of $C\!P$ violation in the decay mode {{B} ^\pm } \rightarrow [{{K} ^+} {{K} ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm , with $h=K,\pi$, is presented, exploiting a data sample of proton–proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9\text {\,fb} ^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for {{B} ^\pm } \rightarrow [{{K} ^+} {{K} ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm and {{B} ^\pm } \rightarrow [{{\uppi } ^+} {{\uppi } ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm decays.The first study of $C\!P$ violation in the decay mode $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^\pm$, with $h=K,\pi$, is presented, exploiting a data sample of proton-proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9$ fb$^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^\pm$ and $B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^\pm$ decays

Search for CPCP violation in the phase space of D0→π−π+π0D^0 \to \pi^-\pi^+\pi^0 decays with the energy test

International audienceA search for $CP$ violation in $D^0 \to \pi^-\pi^+\pi^0$ decays is reported, using $pp$ collision data collected by the LHCb experiment from 2015 to 2018 corresponding to an integrated luminosity of 6$fb^{-1}$. An unbinned model-independent approach provides sensitivity to local $CP$ violation within the two-dimensional phase space of the decay. The method is validated using the Cabibbo-favoured channel \D^0 \to \K^-\pi^+\pi^0 and background regions of the signal mode. The results are consistent with $CP$ symmetry in this decay

Study of the Bose-Einstein correlations of same-sign pions in proton-lead collisions

International audienceCorrelations of same-sign charged particles are analysed using proton-lead collision data collected by the LHCb experiment at a nucleon-nucleon centre-of-mass energy of 5.02 TeV, corresponding to an integrated luminosity of 1.06 nb-1. Bose-Einstein correlations are observed in the form of an enhancement of pair production for same-sign charged pions with a small four-momentum difference squared. The dependence of the correlation radius and the intercept parameter on the reconstructed charged-particle multiplicity is investigated. The measured correlation radii scale linearly with the cube root of the reconstructed charged-particle multiplicity, being compatible with predictions of hydrodynamic models on the collision system evolution

Search for D∗(2007)0→μ+μ−D^{*}(2007)^0\to\mu^+\mu^- in B−→π−μ+μ−B^-\to\pi^-\mu^+\mu^- decays

International audienceThe very rare $D^{*}(2007)^0\to\mu^+\mu^-$ decay is searched for by analysing $B^-\to\pi^-\mu^+\mu^-$ decays. The analysis uses a sample of beauty mesons produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 fb$^{-1}$. The signal signature corresponds to simultaneous peaks in the $\mu^+\mu^-$ and $\pi^-\mu^+\mu^-$ invariant masses. No evidence for an excess of events over background is observed and an upper limit is set on the branching fraction of the decay at ${\cal B}(D^{*}(2007)^0\to\mu^+\mu^-) < 2.6\times 10^{-8}$ at $90\%$ confidence level. This is the first limit on the branching fraction of $D^{*}(2007)^0\to\mu^+\mu^-$ decays and the most stringent limit on $D^{*}(2007)^0$ decays to leptonic final states. The analysis is the first search for a rare charm-meson decay exploiting production via beauty decays

Test of lepton flavour universality using B0→D∗−τ+ντB^0 \to D^{*-}\tau^+\nu_{\tau} decays with hadronic τ\tau channels

The branching fraction $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)$ is measured relative to that of the normalisation mode $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ using hadronic $\tau^+ \to \pi^+\pi^-\pi^+(\pi^0)\bar{\nu}_\tau$ decays in proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2 fb$^{-1}$. The measured ratio is $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)/\mathcal{B}(B^0 \to D^{*-}\pi^+\pi^-\pi^+)= 1.70 \pm 0.10^{+0.11}_{-0.10}$, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ and $B^0 \to D^{*-} \mu^+\nu_\mu$ modes, the lepton universality test, $\mathcal{R}(D^{*-}) \equiv \mathcal{B}(B^0 \to D^{*-}\tau^+\nu_\tau)/\mathcal{B}(B^0 \to D^{*-} \mu^+\nu_\mu)$ is calculated, $$\mathcal{R}(D^{*-}) = 0.247 \pm 0.015 \pm 0.015 \pm 0.012\, ,$$ where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements.The branching fraction B(B0→D*-τ+ντ) is measured relative to that of the normalization mode B0→D*-π+π-π+ using hadronic τ+→π+π-π+(π0)ν¯τ decays in proton-proton collision data at a center-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2  fb-1. The measured ratio is B(B0→D*-τ+ντ)/B(B0→D*-π+π-π+)=1.70±0.10-0.10+0.11, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the B0→D*-π+π-π+ and B0→D*-μ+νμ modes, the lepton universality test R(D*-)≡B(B0→D*-τ+ντ)/B(B0→D*-μ+νμ) is calculated, R(D*-)=0.247±0.015±0.015±0.012, where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements.The branching fraction $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})$ is measured relative to that of the normalisation mode $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ using hadronic $\tau^+ \to \pi^+\pi^-\pi^+(\pi^0)\bar{\nu}_{\tau}$ decays in proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the LHCb experiment, corresponding to an integrated luminosity of 2 fb$^{-1}$. The measured ratio is $\mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})/\mathcal{B}(B^0 \to D^{*-}\pi^+\pi^-\pi^+)= 1.70 \pm 0.10^{+0.11}_{-0.10}$, where the first uncertainty is statistical and the second is related to systematic effects. Using established branching fractions for the $B^0 \to D^{*-}\pi^+\pi^-\pi^+$ and $B^0 \to D^{*-} \mu^+\nu_\mu$ modes, the lepton universality test, $\mathcal{R}(D^{*-}) \equiv \mathcal{B}(B^0 \to D^{*-}\tau^+\nu_{\tau})/\mathcal{B}(B^0 \to D^{*-} \mu^+\nu_\mu)$ is calculated, $$\mathcal{R}(D^{*-}) = 0.247 \pm 0.015 \pm 0.015 \pm 0.012\, ,$$ where the third uncertainty is due to the uncertainties on the external branching fractions. This result is consistent with the Standard Model prediction and with previous measurements