Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations

Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/Gab2-/- double mutant mice-overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML

Association between advanced lung cancer inflammation index and all-cause and cause-specific mortality among asthma patients: a cohort study

BackgroundThe advanced lung cancer inflammation index (ALI), which reflects both inflammation and nutritional status, has an uncertain role in predicting outcomes for asthma patients. This study aimed to evaluate the association between ALI and mortality from all causes, as well as specific causes including cardiovascular disease (CVD) and cancer-related mortality, among individuals with asthma.MethodsWe analyzed data from 4,829 asthma patients who participated in the U.S. National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Cox proportional hazards models were used to assess the relationship between ALI and both all-cause and cause-specific mortality, adjusting for demographic and clinical variables. Additionally, restricted cubic spline models were applied to explore potential nonlinear trends, while segmented Cox models were used to identify threshold effects. A competing risk model further examined the independent association of ALI with CVD mortality.ResultsOver a median follow-up of 7.83 years, a total of 582 deaths from all causes, 151 cardiovascular-related deaths, and 125 cancer-related deaths were recorded. An L-shaped association was observed between ALI and both all-cause and CVD mortality, with thresholds identified at 82.02 for all-cause mortality and 58.40 for CVD mortality. Compared to the lowest quartile of ALI (Q1), patients in the highest quartile (Q4) had a 49% lower risk of all-cause mortality (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.40–0.66) and a 51% reduction in CVD mortality (HR 0.49, 95% CI 0.29–0.83). This protective effect was further confirmed by the competing risk model. No significant association between ALI and cancer mortality was observed (HR 1.01, 95% CI 0.98–1.03).ConclusionALI was significantly and inversely associated with all-cause and CVD mortality in asthma patients, particularly when ALI values were below 82.02 and 58.40, respectively, where the risk of mortality was substantially lower. These findings suggest that ALI may have clinical utility in assessing prognosis for asthma patients, especially in terms of cardiovascular risk evaluation

Transcriptome and Network Changes in Climbers at Extreme Altitudes

Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples

Amplitude Analysis of the Decays D0→π+π−π+π−D^0\to\pi^+\pi^-\pi^+\pi^- and π+π−π0π0\pi^+\pi^-\pi^0\pi^0

Using $e^+e^-$ annihilation data corresponding to an integrated luminosity of 2.93 $\rm fb^{-1}$ taken at the center-of-mass energy $\sqrt{s}=3.773$~GeV with the BESIII detector, a joint amplitude analysis is performed on the decays $D^0\to\pi^+\pi^-\pi^+\pi^-$ and $D^0\to\pi^+\pi^-\pi^0\pi^0$(non-$\eta$). The fit fractions of individual components are obtained, and large interferences among the dominant components of $D^{0}\to a_{1}(1260)\pi$, $D^{0}\to\pi(1300)\pi$, $D^{0}\to\rho(770)\rho(770)$ and $D^{0}\to2(\pi\pi)_{S}$ are found in both channels. With the obtained amplitude model, the $CP$-even fractions of $D^0\to \pi^+\pi^-\pi^+\pi^-$ and $D^0\to\pi^+\pi^-\pi^0\pi^0$(non-$\eta$) are determined to be $(75.2\pm1.1_{\rm stat.}\pm1.5_{\rm syst.})\%$ and $(68.9\pm1.5_{\rm stat.}\pm 2.4_{\rm syst.})\%$, respectively. The branching fractions of $D^0\to \pi^+\pi^-\pi^+\pi^-$ and $D^0\to\pi^+\pi^-\pi^0\pi^0$(non-$\eta$) are measured to be $(0.688\pm0.010_{\rm stat.}\pm 0.010_{\rm syst.})\%$ and $(0.951\pm0.025_{\rm stat.}\pm 0.021_{\rm syst.})\%$, respectively. The amplitude analysis provides an important model for binning strategy in the measurements of the strong phase parameters of $D^0 \to 4\pi$ when used to determine the CKM angle $\gamma (\phi_{3})$ via the $B^{-}\to D K^{-}$ decay

Measurement of the Electromagnetic Transition Form-factors in the decays η′→π+π−l+l−\eta'\rightarrow\pi^+\pi^-l^+l^-

With a sample of $(10087\pm44)\times10^{6}$ $J/\psi$ events accumulated with the BESIII detector, we analyze the decays $\eta'\rightarrow\pi^+\pi^-l^+l^-(l=e,$ $\mu)$ via the process $J/\psi\rightarrow\gamma\eta'$. The branching fractions are measured to be $\mathcal{B}(\eta'\rightarrow\pi^+\pi^-e^+e^-)=(2.45\pm0.02(\rm{stat.})\pm0.08(\rm{syst.})) \times10^{-3}$ and $\mathcal{B}(\eta'\rightarrow\pi^+\pi^-\mu^+\mu^-)=(2.16\pm0.12(\rm{stat.})\pm0.06(\rm{syst.}))\times10^{-5}$, and the ratio is $\frac{\mathcal{B}(\eta'\rightarrow\pi^{+}\pi^{-}e^{+}e^{-})}{\mathcal{B}(\eta'\rightarrow\pi^{+}\pi^{-}\mu^{+}\mu^{-})} = 113.4\pm0.9(\rm{stat.})\pm3.7(\rm{syst.})$. In addition, by combining the $\eta'\rightarrow\pi^+\pi^-e^+e^-$ and $\eta'\rightarrow\pi^+\pi^-\mu^+\mu^-$ decays, the slope parameter of the electromagnetic transition form factor is measured to be $b_{\eta'}=1.30\pm0.19\ (\mathrm{GeV}/c^{2})^{-2}$, which is consistent with previous measurements from BESIII and theoretical predictions from the VMD model. The asymmetry in the angle between the $\pi^+\pi^-$ and $l^+l^-$ decay planes, which has the potential to reveal the $CP$-violation originating from an unconventional electric dipole transition, is also investigated. The asymmetry parameters are determined to be $\mathcal{A}_{CP}(\eta'\rightarrow\pi^+\pi^-e^+e^-)=(-0.21\pm0.73(\rm{stat.})\pm0.01(\rm{syst.}))\%$ and $\mathcal{A}_{CP}(\eta'\rightarrow\pi^+\pi^-\mu^+\mu^-)=(0.62\pm4.71(\rm{stat.})\pm0.08(\rm{syst.}))\%$, implying that no evidence of $CP$-violation is observed at the present statistics. Finally, an axion-like particle is searched for via the decay $\eta'\rightarrow\pi^+\pi^-a, a\rightarrow e^+e^-$, and upper limits of the branching fractions are presented for the mass assumptions of the axion-like particle in the range of $0-500\ \mathrm{MeV}/c^{2}$

First Measurement of the Decay Asymmetry in the pure W-boson-exchange Decay Λc+→Ξ0K+\Lambda_{c}^{+}\to\Xi^{0}K^{+}

Based on $4.4~\text{fb}^{-1}$ of $e^{+}e^{-}$ annihilation data collected at the center-of-mass energies between $4.60$ and $4.70~\text{GeV}$ with the BESIII detector at the BEPCII collider, the pure \textit{W}-boson-exchange decay $\Lambda_{c}^{+}\to\Xi^{0}K^{+}$ is studied with a full angular analysis. The corresponding decay asymmetry is measured for the first time to be $\alpha_{\Xi^{0}K^{+}}=0.01\pm0.16({\rm stat.})\pm0.03({\rm syst.})$. This result reflects the non-interference effect between the $S$- and $P$-wave amplitudes. The phase shift between $S$- and $P$-wave amplitudes has two solutions, which are $\delta_{p}-\delta_{s}=-1.55\pm0.25({\rm stat.})\pm0.05({\rm syst.})~\text{rad}$ or $1.59\pm0.25({\rm stat.})\pm0.05({\rm syst.})~\text{rad}$