The catalytic subunit of the system L1 amino acid transporter (S<i>lc7a5</i>) facilitates nutrient signalling in mouse skeletal muscle

The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass

Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals

Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial

IMPORTANCE: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo. OBJECTIVE: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)—a first-in-class, oral, small-molecule inhibitor of mutant IDH1—vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy. INTERVENTIONS: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life. RESULTS: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0298985

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

BB flavour tagging using charm decays at the LHCb experiment

An algorithm is described for tagging the flavour content at production of neutral $B$ mesons in the LHCb experiment. The algorithm exploits the correlation of the flavour of a $B$ meson with the charge of a reconstructed secondary charm hadron from the decay of the other $b$ hadron produced in the proton-proton collision. Charm hadron candidates are identified in a number of fully or partially reconstructed Cabibbo-favoured decay modes. The algorithm is calibrated on the self-tagged decay modes $B^+ \to J/\psi \, K^+$ and $B^0 \to J/\psi \, K^{*0}$ using $3.0\mathrm{\,fb}^{-1}$ of data collected by the LHCb experiment at $pp$ centre-of-mass energies of $7\mathrm{\,TeV}$ and $8\mathrm{\,TeV}$. Its tagging power on these samples of $B \to J/\psi \, X$ decays is $(0.30 \pm 0.01 \pm 0.01) \%$.Comment: All figures and tables, along with any supplementary material and additional information, are available at http://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-027.htm

Effect of blood glucose level on standardized uptake value (SUV) in F-18- FDG PET-scan : a systematic review and meta-analysis of 20,807 individual SUV measurements

Objectives To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in F-18-FDG-PET scan. Methods A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, F-18-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (200 mg/dl). Results Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p <0.001, p <0.001,) and muscle (p <0.001, p <0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p=0.008, p200 mg/dl had significantly lower SUVmax. Conclusion If BGL is lower than 200mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.Peer reviewe

Identification of beauty and charm quark jets at LHCb

Identification of jets originating from beauty and charm quarks is important for measuring Standard Model processes and for searching for new physics. The performance of algorithms developed to select $b$- and $c$-quark jets is measured using data recorded by LHCb from proton-proton collisions at $\sqrt{s}=7$ TeV in 2011 and at $\sqrt{s}=8$ TeV in 2012. The efficiency for identifying a $b(c)$ jet is about 65%(25%) with a probability for misidentifying a light-parton jet of 0.3% for jets with transverse momentum $p_{\rm T} > 20$ GeV and pseudorapidity $2.2 < \eta < 4.2$. The dependence of the performance on the $p_{\rm T}$ and $\eta$ of the jet is also measured

Test of lepton universality in b→sℓ+ℓ−b \rightarrow s \ell^+ \ell^- decays

The first simultaneous test of muon-electron universality using $B^{+}\rightarrow K^{+}\ell^{+}\ell^{-}$ and $B^{0}\rightarrow K^{*0}\ell^{+}\ell^{-}$ decays is performed, in two ranges of the dilepton invariant-mass squared, $q^{2}$. The analysis uses beauty mesons produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 $\mathrm{fb}^{-1}$. Each of the four lepton universality measurements reported is either the first in the given $q^{2}$ interval or supersedes previous LHCb measurements. The results are compatible with the predictions of the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-046.html (LHCb public pages

Updated measurements of exclusive J/ψ and ψ(2S) production cross-sections in pp collisions at √s = 7 TeV

The differential cross-section as a function of rapidity has been measured for the exclusive production of J/ψ and ψ(2S) mesons in proton–proton collisions at √s = 7 TeV, using data collected by the LHCb experiment, corresponding to an integrated luminosity of 930 pb−1. The cross-sections times branching fractions to two muons having pseudorapidities between 2.0 and 4.5 are measured to be where the first uncertainty is statistical and the second is systematic. The measurements agree with next-to-leading order QCD predictions as well as with models that include saturation effects