A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development

Observation of B→D(∗)K−KS0{B\to D^{(*)} K^- K^{0}_S} decays using the 2019-2022 Belle II data sample

We present a measurement of the branching fractions of four $B^{0,-}\to D^{(*)+,0} K^- K^{0}_S$ decay modes. The measurement is based on data from SuperKEKB electron-positron collisions at the $\Upsilon(4S)$ resonance collected with the Belle II detector and corresponding to an integrated luminosity of ${362~\text{fb}^{-1}}$. The event yields are extracted from fits to the distributions of the difference between expected and observed $B$ meson energy to separate signal and background, and are efficiency-corrected as a function of the invariant mass of the $K^-K_S^0$ system. We find the branching fractions to be: $$\text{B}(B^-\to D^0K^-K_S^0)=(1.89\pm 0.16\pm 0.10)\times 10^{-4},$$ $$\text{B}(\overline B{}^0\to D^+K^-K_S^0)=(0.85\pm 0.11\pm 0.05)\times 10^{-4},$$ $$\text{B}(B^-\to D^{*0}K^-K_S^0)=(1.57\pm 0.27\pm 0.12)\times 10^{-4},$$ $$\text{B}(\overline B{}^0\to D^{*+}K^-K_S^0)=(0.96\pm 0.18\pm 0.06)\times 10^{-4},$$ where the first uncertainty is statistical and the second systematic. These results include the first observation of $\overline B{}^0\to D^+K^-K_S^0$, $B^-\to D^{*0}K^-K_S^0$, and $\overline B{}^0\to D^{*+}K^-K_S^0$ decays and a significant improvement in the precision of $\text{B}(B^-\to D^0K^-K_S^0)$ compared to previous measurements

Reconstruction of B→ρℓνℓB \to \rho \ell \nu_\ell decays identified using hadronic decays of the recoil BB meson in 2019 -- 2021 Belle II data

We present results on the semileptonic decays $B^0 \to \rho^- \ell^+ \nu_\ell$ and $B^+ \to \rho^0 \ell^+ \nu_\ell$ in a sample corresponding to 189.9/fb of Belle II data at the SuperKEKB $e^- e^+$ collider. Signal decays are identified using full reconstruction of the recoil $B$ meson in hadronic final states. We determine the total branching fractions via fits to the distributions of the square of the "missing" mass in the event and the dipion mass in the signal candidate and find ${\mathcal{B}(B^0\to\rho^-\ell^+ \nu_\ell) = (4.12 \pm 0.64(\mathrm{stat}) \pm 1.16(\mathrm{syst})) \times 10^{-4}}$ and ${\mathcal{B}({B^+\to\rho^0\ell^+\nu_\ell}) = (1.77 \pm 0.23 (\mathrm{stat}) \pm 0.36 (\mathrm{syst})) \times 10^{-4}}$ where the dominant systematic uncertainty comes from modeling the nonresonant $B\to (\pi\pi)\ell^+\nu_\ell$ contribution

Angular analysis of B+→ρ+ρ0B^+ \to \rho^+\rho^0 decays reconstructed in 2019, 2020, and 2021 Belle II data

We report on a Belle II measurement of the branching fraction ($\mathcal{B}$), longitudinal polarization fraction ($f_L$), and CP asymmetry ($\mathcal{A}_{CP}$) of $B^+\to \rho^+\rho^0$ decays. We reconstruct $B^+\to \rho^+(\to \pi^+\pi^0(\to \gamma\gamma))\rho^0(\to \pi^+\pi^-)$ decays in a sample of SuperKEKB electron-positron collisions collected by the Belle II experiment in 2019, 2020, and 2021 at the $\Upsilon$(4S) resonance and corresponding to 190 fb$^{-1}$ of integrated luminosity. We fit the distributions of the difference between expected and observed $B$ candidate energy, continuum-suppression discriminant, dipion masses, and decay angles of the selected samples, to determine a signal yield of $345 \pm 31$ events. The signal yields are corrected for efficiencies determined from simulation and control data samples to obtain $\mathcal{B}(B^+ \to \rho^+\rho^0) = [23.2^{+\ 2.2}_{-\ 2.1} (\rm stat) \pm 2.7 (\rm syst)]\times 10^{-6}$,$f_L = 0.943 ^{+\ 0.035}_{-\ 0.033} (\rm stat)\pm 0.027(\rm syst)$, and$\mathcal{A}_{CP}=-0.069 \pm 0.068(\rm stat) \pm 0.060 (\rm syst)$. The results agree with previous measurements. This is the first measurement of$\mathcal{A}_{CP}$in$B^+\to \rho^+\rho^0$ decays reported by Belle II

Determination of ∣Vub∣|V_{ub}| from untagged B0→π−ℓ+νℓB^0\to\pi^- \ell^+ \nu_{\ell} decays using 2019-2021 Belle II data

We present an analysis of the charmless semileptonic decay $B^0\to\pi^- \ell^+ \nu_{\ell}$, where $\ell = e, \mu$, from 198.0 million pairs of $B\bar{B}$ mesons recorded by the Belle II detector at the SuperKEKB electron-positron collider. The decay is reconstructed without identifying the partner $B$ meson. The partial branching fractions are measured independently for $B^0\to\pi^- e^+ \nu_{e}$ and $B^0\to\pi^- \mu^+ \nu_{\mu}$ as functions of $q^{2}$ (momentum transfer squared), using 3896 $B^0\to\pi^- e^+ \nu_{e}$ and 5466 $B^0\to\pi^- \mu^+ \nu_{\mu}$ decays. The total branching fraction is found to be $(1.426 \pm 0.056 \pm 0.125) \times 10^{-4}$ for $B^0\to\pi^- \ell^+ \nu_{\ell}$ decays, where the uncertainties are statistical and systematic, respectively. By fitting the measured partial branching fractions as functions of $q^{2}$, together with constraints on the nonperturbative hadronic contribution from lattice QCD calculations, the magnitude of the Cabibbo-Kobayashi-Maskawa matrix element $V_{ub}$, $(3.55 \pm 0.12 \pm 0.13 \pm 0.17) \times 10^{-3}$, is extracted. Here, the first uncertainty is statistical, the second is systematic and the third is theoretical

Measurement of the branching fractions and CPCP asymmetries of B+→π+π0B^+ \rightarrow \pi^+ \pi^0 and B+→K+π0B^+ \rightarrow K^+ \pi^0 decays in 2019-2021 Belle II data

We determine the branching fractions ${\mathcal{B}}$ and $CP$ asymmetries ${\mathcal{A}_{{\it CP}}}$ of the decays $B^+ \rightarrow \pi^+ \pi^0$ and $B^+ \rightarrow K^+ \pi^0$. The results are based on a data set containing 198 million bottom-antibottom meson pairs corresponding to an integrated luminosity of $190\;\text{fb}^{-1}$ recorded by the Belle II detector in energy-asymmetric electron-positron collisions at the $\Upsilon (4S)$ resonance. We measure ${\mathcal{B}(B^+ \rightarrow \pi^+ \pi^0) = (6.12 \pm 0.53 \pm 0.53)\times 10^{-6}}$, ${\mathcal{B}(B^+ \rightarrow K^+ \pi^0) = (14.30 \pm 0.69 \pm 0.79)\times 10^{-6}}$, ${\mathcal{A}_{{\it CP}}(B^+ \rightarrow \pi^+ \pi^0) = -0.085 \pm 0.085 \pm 0.019}$, and ${\mathcal{A}_{{\it CP}}(B^+ \rightarrow K^+ \pi^0) = 0.014 \pm 0.047 \pm 0.010}$, where the first uncertainties are statistical and the second are systematic. These results improve a previous Belle II measurement and agree with the world averages

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Measurement of the branching fraction for the decay B→K∗(892)ℓ+ℓ−B \to K^{\ast}(892)\ell^+\ell^- at Belle II

We report a measurement of the branching fraction of $B \to K^{\ast}(892)\ell^+\ell^-$ decays, where $\ell^+\ell^- = \mu^+\mu^-$ or $e^+e^-$, using electron-positron collisions recorded at an energy at or near the $\Upsilon(4S)$ mass and corresponding to an integrated luminosity of $189$ fb$^{-1}$. The data was collected during 2019--2021 by the Belle II experiment at the SuperKEKB $e^{+}e^{-}$ asymmetric-energy collider. We reconstruct $K^{\ast}(892)$ candidates in the $K^+\pi^-$, $K_{S}^{0}\pi^+$, and $K^+\pi^0$ final states. The signal yields with statistical uncertainties are $22\pm 6$, $18 \pm 6$, and $38 \pm 9$ for the decays $B \to K^{\ast}(892)\mu^+\mu^-$, $B \to K^{\ast}(892)e^+e^-$, and $B \to K^{\ast}(892)\ell^+\ell^-$, respectively. We measure the branching fractions of these decays for the entire range of the dilepton mass, excluding the very low mass region to suppress the $B \to K^{\ast}(892)\gamma(\to e^+e^-)$ background and regions compatible with decays of charmonium resonances, to be \begin{equation} {\cal B}(B \to K^{\ast}(892)\mu^+\mu^-) = (1.19 \pm 0.31 ^{+0.08}_{-0.07}) \times 10^{-6}, {\cal B}(B \to K^{\ast}(892)e^+e^-) = (1.42 \pm 0.48 \pm 0.09)\times 10^{-6}, {\cal B}(B \to K^{\ast}(892)\ell^+\ell^-) = (1.25 \pm 0.30 ^{+0.08}_{-0.07}) \times 10^{-6}, \end{equation} where the first and second uncertainties are statistical and systematic, respectively. These results, limited by sample size, are the first measurements of $B \to K^{\ast}(892)\ell^+\ell^-$ branching fractions from the Belle II experiment

Measurements of the branching fractions for B→K∗γB \to K^{*}\gamma decays at Belle II

This paper reports a study of $B \to K^{*}\gamma$ decays using $62.8\pm 0.6$ fb$^{-1}$ of data collected during 2019--2020 by the Belle II experiment at the SuperKEKB $e^{+}e^{-}$ asymmetric-energy collider, corresponding to $(68.2 \pm 0.8) \times 10^6$ $B\overline{B}$ events. We find $454 \pm 28$, $50 \pm 10$, $169 \pm 18$, and $160 \pm 17$ signal events in the decay modes $B^{0} \to K^{*0}[K^{+}\pi^{-}]\gamma$, $B^{0} \to K^{*0}[K^0_{\rm S}\pi^{0}]\gamma$, $B^{+} \to K^{*+}[K^{+}\pi^{0}]\gamma$, and $B^{+} \to K^{*+}[K^{+}\pi^{0}]\gamma$, respectively. The uncertainties quoted for the signal yield are statistical only. We report the branching fractions of these decays: $$\mathcal{B} [B^{0} \to K^{*0}[K^{+}\pi^{-}]\gamma] = (4.5 \pm 0.3 \pm 0.2) \times 10^{-5},$$ $$\mathcal{B} [B^{0} \to K^{*0}[K^0_{\rm S}\pi^{0}]\gamma] = (4.4 \pm 0.9 \pm 0.6) \times 10^{-5},$$ $$\mathcal{B} [B^{+} \to K^{*+}[K^{+}\pi^{0}]\gamma] = (5.0 \pm 0.5 \pm 0.4)\times 10^{-5},\text{ and}$$ $$\mathcal{B} [B^{+} \to K^{*+}[K^0_{\rm S}\pi^{+}]\gamma] = (5.4 \pm 0.6 \pm 0.4) \times 10^{-5},$$ where the first uncertainty is statistical, and the second is systematic. The results are consistent with world-average values