A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis.

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD

SDSS J013127.34−-032100.1: A newly discovered radio-loud quasar at z=5.18z=5.18 with extremely high luminosity

Only very few z>5 quasars discovered to date are radio-loud, with a radio-to-optical flux ratio (radio-loudness parameter) higher than 10. Here we report the discovery of an optically luminous radio-loud quasar, SDSS J013127.34-032100.1 (J0131-0321 in short), at z=5.18+-0.01 using the Lijiang 2.4m and Magellan telescopes. J0131-0321 has a spectral energy distribution consistent with that of radio-loud quasars. With an i-band magnitude of 18.47 and radio flux density of 33 mJy, its radio-loudness parameter is ~100. The optical and near-infrared spectra taken by Magellan enable us to estimate its bolometric luminosity to be L_bol ~ 1.1E48 erg/s, approximately 4.5 times greater than that of the most distant quasar known to date. The black hole mass of J0131-0321 is estimated to be 2.7E9 solar masses, with an uncertainty up to 0.4 dex. Detailed physical properties of this high-redshift, radio-loud, potentially super-Eddington quasar can be probed in the future with more dedicated and intensive follow-up observations using multi-wavelength facilities.Comment: 5 pages, 3 figures, accepted to ApJ

The controlling nutritional status score predicts postoperative mortality in patients with ruptured abdominal aortic aneurysm: a retrospective study

BackgroundRuptured abdominal aortic aneurysms (rAAAs) are challenging for vascular surgeons because they have a high mortality rate. In many diseases, nutritional status is closely associated with prognosis. The Controlling Nutritional Status (CONUT) screening tool score is a prognostic factor in some malignant and chronic diseases; however, the impact of nutritional status on rAAA has not yet been reported. In this study, we explored the relationship between the CONUT score and the postoperative prognosis of patients with rAAA.MethodsThis was a retrospective review of 39 patients with rAAA who underwent surgical treatment from March 2018 to September 2021 at one center. Patient characteristics, nutritional status (CONUT score), and postoperative status were recorded. The patients were divided into groups A and B based on the CONUT score. The baseline characteristics of the two groups were compared, and Cox proportional hazards and logistic regression analyses were used to determine independent predictors of mid-term mortality and complications, respectively.ResultsThe overall mid-term mortality rate was 28.21% (11/39). Compared with group A, group B had higher intraoperative (P = 0.047) and mid-term mortality (P = 0.033) rates. The univariate analysis showed that age [hazard ratio (HR), 1.098; 95% confidence interval (CI), 1.019–1.182; P = 0.014], CONUT score (HR, 1.316; 95% CI, 1.027–1.686; P = 0.03), and surgical procedure (HR, 0.127; 95% CI, 0.016–0.992; P = 0.049) were associated with mid-term mortality, whereas the multivariate analysis showed that the CONUT score (HR, 1.313; 95% CI, 1.009–1.710; P = 0.043) was an independent predictor of mid-term mortality. The multivariate logistic regression analysis did not reveal any associations with complications. The Kaplan–Meier curves showed that group B had a lower mid-term survival rate (log-rank P = 0.024).ConclusionMalnutrition is closely associated with the prognosis of patients with rAAA, and the CONUT score can be used to predict mid-term mortality

Hidden in the bamboo: A new parachuting frog (Rhacophoridae, Rhacophorus) from the borderlands of western China, with comments on the taxonomy of R. rhodopus

The Gaoligong Mountains are characterized by large variations in elevation and topography, which support high levels of biodiversity and endemism that remain largely understudied. Herein, based on the integration of morphological comparisons and phylogenetic reconstruction, we describe a new species of Rhacophorus from the northern Gaoligong Mountains, Yunnan Province, China. The new species, Rhacophorus dulongensis sp. nov., is morphologically distinguishable from its congeners based on the differences in body size, head length, tibia length, snout and tongue shape, toe webbing formula and coloration, ventral skin texture and coloration, dorsal pattern and coloration, body macroglands, iris coloration, and pattern of markings on flanks. Phylogenetically, it differs from its congeners by uncorrected p-distances of >4.8% for the 16S rRNA gene fragment. Rhacophorus dulongensis sp. nov. is likely to be found in Myanmar, considering its type locality lies close to the China-Myanmar border. The phylogenetic analysis revealed that the “widespread” species, R. rhodopus, is a species complex and a composite of five distinct lineages. The results revealed that R. napoensis is also found in Vietnam, making it a new country record for Vietnam. Interestingly, R. dulongensis sp. nov. likely breeds in bamboo, a hidden behavioral characteristic that makes them easy to overlook. Given the ongoing habitat loss and degradation in the region, further biological exploration is urgently needed in the Gaoligong Mountains as a biodiversity reservoir

Towards a global One Health index: a potential assessment tool for One Health performance

BACKGROUND: A One Health approach has been increasingly mainstreamed by the international community, as it provides for holistic thinking in recognizing the close links and inter-dependence of the health of humans, animals and the environment. However, the dearth of real-world evidence has hampered application of a One Health approach in shaping policies and practice. This study proposes the development of a potential evaluation tool for One Health performance, in order to contribute to the scientific measurement of One Health approach and the identification of gaps where One Health capacity building is most urgently needed. METHODS: We describe five steps towards a global One Health index (GOHI), including (i) framework formulation; (ii) indicator selection; (iii) database building; (iv) weight determination; and (v) GOHI scores calculation. A cell-like framework for GOHI is proposed, which comprises an external drivers index (EDI), an intrinsic drivers index (IDI) and a core drivers index (CDI). We construct the indicator scheme for GOHI based on this framework after multiple rounds of panel discussions with our expert advisory committee. A fuzzy analytical hierarchy process is adopted to determine the weights for each of the indicators. RESULTS: The weighted indicator scheme of GOHI comprises three first-level indicators, 13 second-level indicators, and 57 third-level indicators. According to the pilot analysis based on the data from more than 200 countries/territories the GOHI scores overall are far from ideal (the highest score of 65.0 out of a maximum score of 100), and we found considerable variations among different countries/territories (31.8–65.0). The results from the pilot analysis are consistent with the results from a literature review, which suggests that a GOHI as a potential tool for the assessment of One Health performance might be feasible. CONCLUSIONS: GOHI—subject to rigorous validation—would represent the world’s first evaluation tool that constructs the conceptual framework from a holistic perspective of One Health. Future application of GOHI might promote a common understanding of a strong One Health approach and provide reference for promoting effective measures to strengthen One Health capacity building. With further adaptations under various scenarios, GOHI, along with its technical protocols and databases, will be updated regularly to address current technical limitations, and capture new knowledge. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40249-022-00979-9

S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.</p

Study of J/ψJ/\psi and ψ(3686)→Σ(1385)0Σˉ(1385)0\psi(3686)\rightarrow\Sigma(1385)^{0}\bar\Sigma(1385)^{0} and Ξ0Ξˉ0\Xi^0\bar\Xi^{0}

We study the decays of $J/\psi$ and $\psi(3686)$ to the final states $\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$ and $\Xi^0\bar\Xi^{0}$ based on a single baryon tag method using data samples of $(1310.6 \pm 7.0) \times 10^{6}$ $J/\psi$ and $(447.9 \pm 2.9) \times 10^{6}$ $\psi(3686)$ events collected with the BESIII detector at the BEPCII collider. The decays to $\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$ are observed for the first time. The measured branching fractions of $J/\psi$ and $\psi(3686)\rightarrow\Xi^0\bar\Xi^{0}$ are in good agreement with, and much more precise, than the previously published results. The angular parameters for these decays are also measured for the first time. The measured angular decay parameter for $J/\psi\rightarrow\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$, $\alpha =-0.64 \pm 0.03 \pm 0.10$, is found to be negative, different to the other decay processes in this measurement. In addition, the "12\% rule" and isospin symmetry in the $J/\psi$ and $\psi(3686)\rightarrow\Xi\bar\Xi$ and $\Sigma(1385)\bar{\Sigma}(1385)$ systems are tested.Comment: 11 pages, 7 figures. This version is consistent with paper published in Phys.Lett. B770 (2017) 217-22

Search for C-parity violation in J/ψ→γγJ/ \psi \to \gamma\gamma and γϕ \gamma \phi

Using $1.06\times10^8$ $\psi(3686)$ events recorded in $e^{+}e^{-}$ collisions at $\sqrt{s}=$ 3.686 GeV with the BESIII at the BEPCII collider, we present searches for C-parity violation in $J/\psi \to \gamma\gamma$ and $\gamma \phi$ decays via $\psi(3686) \to J/\psi \pi^+\pi^-$. No significant signals are observed in either channel. Upper limits on the branching fractions are set to be $\mathcal{B}(J/\psi \to \gamma\gamma) < 2.7 \times 10^{-7}$ and $\mathcal{B}(J/\psi \to \gamma\phi) < 1.4 \times 10^{-6}$ at the 90\% confidence level. The former is one order of magnitude more stringent than the previous upper limit, and the latter represents the first limit on this decay channel.Comment: 7 pages, 2 figure