Background
This study aimed to analyze the change of serum uric acid (SUA) level post peritoneal dialysis (PD), and the correlation between follow‐up SUA and prognosis in patients with PD.
Methods
A ...total of 1402 patients with PD were evaluated. We graded SUA levels into four grades at baseline, 6 months, 12 months, 18 months, and 24 months post PD, and then compared all‐cause mortality and cardiovascular mortality among patients with different SUA grades at each time point. Kaplan–Meier and Cox proportional‐hazards regression models were used in the analysis.
Results
The SUA levels were 7.97 ± 1.79, 7.12 ± 1.48, 7.05 ± 1.33, 7.01 ± 1.30, and 6.93 ± 1.26 mg/dl at baseline, 6, 12, 18, and 24 months, respectively. There was significant difference on all‐cause mortality among patients with PD with different graded SUA levels at 6 months post PD (p = 0.010), and the all‐cause mortality was lowest in patients with the grade of 5.65 mg/dl ≤ SUA <7.13 mg/dl.
Conclusion
SUA level decreased after PD during follow‐up. At 6 months post PD, the grade of 5.65 mg/dl ≤ SUA <7.13 mg/dl was appropriate for better patients' survival.
•Experimental removal or addition of 50% of the snow pack was conducted throughout the winter.•A rapid and transient response of microbes to temperature was found under snow manipulation.•Snow ...addition enhanced soil CO2 effluxes only when soil temperature significantly increased.•PLFA analysis confirmed transient changes in microbial communities by snow addition.•Cumulative soil CO2 effluxes were not affected by altered snow depth.
Global climate change is altering snow depth in winter, which could significantly affect soil respiration and microbial communities. However, belowground responses are still uncertain as they depend on the thermal effects on soils, the acclimation of soil microbial communities and ecosystem type. Here, we conducted a snow manipulation experiment including 50% removal of snowpack (mean snow depth after treatment was 3.1 ± 0.7 cm), ambient snow (mean snow depth was 6.3 ± 0.7 cm), and 50% increase of snowpack (mean snow depth after treatment was 9.6 ± 1.5 cm) to explore the effects of altered snow depth on winter soil respiration and microbial communities in a mid-latitude plantation forest with continental climate with dry winters. Winter soil CO2 effluxes varied from 0.09 to 0.84 µmol m−2 s−1 with a mean of 0.32 ± 0.07 µmol m−2 s−1. The cumulative soil CO2 effluxes from 11 December 2014 to 21 March 2015 were 27.3 ± 1.1, 26.5 ± 2.1, and 29.5 ± 1.3 g C m−2 under reduced, ambient and added snowpack, which corresponded to 5.7 ± 0.2%, 5.5 ± 0.3%, and 5.8 ± 0.1% of the annual soil CO2 effluxes, respectively. Our one-year observation results suggested that although snow reduction decreased soil temperature, microbial biomass carbon (MBC) and soil respiration did not change, suggesting microbial adaptation to cold conditions between −4 °C and −1 °C. In contrast, snow addition increased soil temperature, MBC, and soil respiration. Microbial community structure (F/B, ratio of fungi to bacteria) was also changed and soil enzymatic (β-glucosidase) activities increased under snow addition. However, these effects were short-lived and disappeared when soil temperature did not differ between the addition and control plots at the 14th day after treatment. These results indicated that the responses of soil microbial communities and respiratory activities to changing soil temperature were rapid and the response of soil respiration to snow addition was transient. Consequently, altered snow depth did not affect cumulative soil CO2 effluxes. Our study suggests that wintertime soil respiration rates are generally low and snow manipulation has minor effects on soil CO2 efflux, soil temperature (the determinant driver of wintertime soil CO2 efflux) and soil microbial biomass at our site.
Macrophages are immune cells responsible for tissue debridement and fighting infection. Clofazimine, an FDA-approved antibiotic, accumulates and precipitates as rod-shaped, crystal-like drug ...inclusions within macrophage lysosomes. Drug treatment as well as pathophysiological states could induce changes in macrophage mechanical property which in turn impact their phenotype and function. Here we report the use of acoustic tweezing cytometry as a new approach for in situ mechanical phenotyping of macrophages and for targeted macrophage cytotripsy. Acoustic tweezing cytometry applies ultrasound pulses to exert controlled forces to individual cells via integrin-bound microbubbles, enabling a creep test for measuring cellular mechanical property or inducing irreversible changes to the cells. Our results revealed that macrophages with crystal-like drug inclusions became significantly softer with higher cell compliance, and behaved more elastic with faster creep and recovery time constants. On the contrary, phagocytosis of solid polyethylene microbeads or treatment with soluble clofazimine rendered macrophages stiffer. Most notably, application of ultrasound pulses of longer duration and higher amplitude in ATC actuated the integrin-bound microbubbles to mobilize the crystal-like drug inclusions inside macrophages, turning the rod-shaped drug inclusions into intracellular microblender that effectively destructed the cells. This phenomenon of acoustic mechanopharmaceutical cytotripsy may be exploited for ultrasound activated, macrophage-directed drug release and delivery.
More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients ...with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.
Synopsis
Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.
XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.
XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.
XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models.
Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.
Nitro-oleic acid (OA-NO(2)) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO(2) exerts cell signaling actions as a result of ...its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature.
The present study sought to investigate the protective role of OA-NO(2) in angiotensin (Ang) II-induced hypertension.
We show that systemic administration of OA-NO(2) results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO(2) significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT(1)R)-mediated signaling because vascular contraction by other G-protein-coupled receptors is not altered in response to OA-NO(2) treatment. From the mechanistic viewpoint, OA-NO(2) lowers Ang II-induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)gamma activation. Rather, OA-NO(2), but not OA, specifically binds to the AT(1)R, reduces heterotrimeric G-protein coupling, and inhibits IP(3) (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor.
These results demonstrate that OA-NO(2) diminishes the pressor response to Ang II and inhibits AT(1)R-dependent vasoconstriction, revealing OA-NO(2) as a novel antagonist of Ang II-induced hypertension.
Cellular rheological properties affect cell function and are reflective of cell status. It is challenging to perform multiplexed single‐cell rheology probing with high controllability, particularly ...for adherent cells. A surface acoustic wave (SAW)‐based method is presented for this purpose. The method integrates the potent micromanipulation ability of acoustic waves in a microfluidic chamber with the ability of cell‐anchored microbeads to concentrate the acoustic energy to deform the cell. Two strategies are developed for placing a targeted microbead at a desired position on the cell membrane. The power‐law rheological dynamics with plastic components are applied to fit the creep (during the mechanical loading) and relaxation (after force removal) responses of the cell. With more than 400 measurements of adherent cells and each with detailed dynamics, a full range of viscoelastic behaviors of cells far beyond the typical rheology of previously reported adherent cells and unexpected negative plastic compliance is observed. The developed method supports in‐depth investigations of biomechanics at the cellular and subcellular levels, with considerable potential for extension to mechanical force‐based cell function regulation.
Multiplexed single‐cell rheology probing is achieved using surface acoustic waves (SAWs). Targeted microbeads are first located to adhered cells forming binding with cell surface proteins either on top or on the side, and then pushed by acoustic waves to deform cells for cell rheology measurement. The method allows for high‐throughput semi‐quantitative analysis of cell rheology.
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various ...treatments. However, TSGs remain to be systemically determined in lung cancer. Here, we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth
in vitro
and tumorigenesis
in vivo
. Mechanistically, GATA6 upregulated p53 and p21 mRNA while it inhibited AKT activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic slowdown of growth rate of established lung tumor xenograft
in vivo
.
Objectives: To investigate the efficacy and safety of an improved ultrasound-guided pulsed radiofrequency (PRF) and nerve block (NB) for patients with pudendal neuralgia (PN). Methods: This ...retrospective analysis included 88 adults with PN treated in the Pain Department of Southwest Hospital from November 2011 to June 2021, with treatment including NB (n = 40) and PRF (n = 48). The primary outcome variable was pain severity, measured by a standardized visual analog scale (VAS). VAS values were collected at 1, 3, 7, and 14 days and 1 and 3 months after patients were treated with NB or PRF. Results: Compared with patients treated with NB (n = 40) and those treated with PRF (n = 48), no significant difference in pain reduction was observed in the short term (p = 0.739 and 0.981, at 1 and 3 days, respectively); however, in the medium and long term (1 to 3 months), there were statistically significant improvements in the PRF group over the NB group (p < 0.001). Moreover, it was noted that the average pain severity of primary PN and PN due to sacral perineurial cyst was significantly reduced with PRF therapy in the medium and long term when compared to other secondary PNs, including surgery, trauma, and diabetes. Discussion: The ultrasound-guided, improved, and innovative PRF/NB puncture path technique allows for gentler stimulation and faster identification of the pudendal nerve. The PRF technique may provide better treatments for primary PN and sacral perineurial cyst causing secondary PN in the medium and long term.
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