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The study aimed to investigate the effect of early mobilization combined with early nutrition (EMN) on intensive care unit-acquired weakness (ICU-AW) in intensive care unit (ICU) settings compared with early mobilization (EM) or routine care. A prospective, dual-center, randomized controlled trial was conducted. The control group underwent standard care without a pre-established routine for mobilization and nutrition. The EM group underwent early, individualized, progressive mobilization within 24 h of ICU admission. The EMN group underwent early mobilization, similar to the EM group plus guideline-based early nutrition (within 48 h of ICU admission). The primary outcome was the occurrence of ICU-AW at discharge from the ICU. Secondary outcomes included muscle strength, functional independence, organ failure, nutritional status, duration of mechanical ventilation (MV), length of ICU stay, and ICU mortality at ICU discharge. A total of 150 patients were enrolled and equally distributed into the three groups. Patients undergoing routine care only were more susceptible to ICU-AW upon ICU discharge than those in the EM or EMN groups (16% vs. 2%; p = 0.014 for both), and had a lower Barthel Index than others (control vs. EM/EMN: 57.5 vs 70.0; p = 0.022). The EMN group had improved muscle strength (p = 0.028) and better nutritional status than the control group (p = 0.031). Both interventions were associated with a lower ICU-AW (EM vs. control: p = 0.027, OR [95% CI] = 0.066 [0.006-0.739]; EMN vs. control: p = 0.016, OR [95% CI] = 0.065 [0.007-0.607]). EM and EMN had positive effects. There was little difference between the effects of EM and EMN, except for muscle strength improvement. Both EM and EMN may lead to a lower occurrence of ICU-AW and better functional independence than standard care. EMN might benefit nutritional status more than usual care and promote improvement in muscle strength.

This paper is devoted to the study of the shape of the free boundary for a three-dimensional axisymmetric incompressible impinging jet. To be more precise, we will show that the free boundary is convex to the fluid, provided that the uneven ground is concave to the fluid.

STING (stimulator of interferon genes) is a central molecule that binds to cyclic dinucleotides produced by the cyclic GMP-AMP synthase (cGAS) to activate innate immunity against microbial infection. Here we report that STING harbors classic LC-3 interacting regions (LIRs) and mediates autophagy through its direct interaction with LC3. We observed that poly(dA:dT), cGAMP, and HSV-1 induced STING-dependent autophagy and degradation of STING immediately after TBK1 activation. STING induces non-canonical autophagy that is dependent on ATG5, whereas other autophagy regulators such as Beclin1, Atg9a, ULK1, and p62 are dispensable. LIR mutants of STING abolished its interaction with LC3 and its activation of autophagy. Also, mutants that abolish STING dimerization and cGAMP-binding diminished the STING-LC3 interaction and subsequent autophagy, suggesting that STING activation is indispensable for autophagy induction. Our results thus uncover dual functions of STING in activating the immune response and autophagy, and suggest that STING is involved in ensuring a measured innate immune response.

C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.

Radiofrequency ablation (RFA) promotes tumor antigen-specific T cell responses and enhances the effect of immunotherapy in preclinical settings. Here we report that the existence of remnant tumor masses due to incomplete RFA (iRFA) is associated with earlier new metastases and poor survival in patients with colorectal cancer liver metastases (CRCLM). Using mouse models, we demonstrate that iRFA promotes tumor progression and hinders the efficacy of anti-PD-1 therapy. Immune analysis reveals that iRFA induces sustained local inflammation with predominant myeloid suppressor cells, which inhibit T cell function in tumors. Mechanistically, tumor cell-derived CCL2 is critical for the accumulation of monocytes and tumor-associated macrophages (TAMs). The crosstalk between TAMs and tumor cells enhances the CCL2 production by tumor cells. Furthermore, we find that administration of a CCR2 antagonist or the loss of CCL2 expression in tumor cells enhances the antitumor activity of PD-1 blockade, providing a salvage alternative for residual tumors after iRFA. Radiofrequency ablation is used to treat metastatic colorectal cancer. In this study, the authors show that incomplete ablation of tumours results in metastases and show in mouse models that the chemokine CCL2 recruits myeloid cells to the partially ablated tumours, which can block T cell function.

Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity. Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.

To evaluate the safety and efficacy of robotic-assisted laparoscopic pyeloplasty (RALP) in infants under 6 months of age with ureteropelvic junction obstruction (UPJO). A retrospective analysis was conducted on infants aged ≤ 6 months who underwent RALP for UPJO between March 2021 and June 2024. Surgical indications included ultrasonographic evidence of severe hydronephrosis, progressive postnatal hydronephrosis, or symptoms related to hydronephrosis compression. Data on demographic characteristics, surgical details, postoperative complications, and follow-up outcomes were analyzed. Among 52 infants (34 male, 18 female), the median age was 70 days (IQR: 45, 107; 95% CI: 61, 87) and mean weight was 5.90 ± 1.39 kg (95% CI: 5.5, 6.3). All procedures were completed robotically without conversion. The mean operative time was 189 ± 34 min (95% CI: 177, 197) with median blood loss of 8.5 mL (IQR: 6.4, 11.3; 95% CI: 7.7, 9.7). Double-J stent placement (4.7 F) was successful in all cases. The median hospital stay was 4.0 days (IQR: 3.0, 4.0; 95% CI: 3.0, 4.0). Postoperative complications occurred in 7 patients (13.5%), including Clavien-Madadi grade I (n = 2), II (n = 4), and III (n = 1). At 3-month follow-up, the mean anteroposterior diameter (APD) decreased from 30.6 ± 8.6 mm to 11.8 ± 6.8 mm (P < 0.0001), and the mean parenchymal thickness increased from 2.4 ± 1.2 mm to 6.6 ± 2.1 mm (P < 0.0001). Success rate was 100% at median follow-up of 21 months (IQR: 16, 26; 95% CI: 19,23). RALP represents a safe and effective treatment option for UPJO in infants age ≤ 6 months, demonstrating excellent short-term outcomes and acceptable complication rates.

Mobile manipulation has a broad range of applications in robotics. However, it is usually more challenging than fixed-base manipulation due to the complex coordination of a mobile base and a manipulator. Although recent works have demonstrated that deep reinforcement learning is a powerful technique for fixed-base manipulation tasks, most of them are not applicable to mobile manipulation. This paper investigates how to leverage deep reinforcement learning to tackle whole-body mobile manipulation tasks in unstructured environments using only on-board sensors. A novel mobile manipulation system which integrates the state-of-the-art deep reinforcement learning algorithms with visual perception is proposed. It has an efficient framework decoupling visual perception from the deep reinforcement learning control, which enables its generalization from simulation training to real-world testing. Extensive simulation and experiment results show that the proposed mobile manipulation system is able to grasp different types of objects autonomously in various simulation and real-world scenarios, verifying the effectiveness of the proposed mobile manipulation system.

With or without biomarker-directed toripalimab plus chemotherapy could bring significant clinical benefit and acceptable safety profile compared with chemotherapy as first-line treatment for patients with extensive-stage small-cell lung-cancer (ES-SCLC) were demonstrated in EXTENTORCH trial. However, its cost-effective remains uncleared. The current analysis aimed to evaluate the economic value of intratumor heterogeneity (ITH) testing directed toripalimab plus chemotherapy as first-line treatment for patients with ES-SCLC from the Chinese health-care system perspective. A mathematical decision model-based cost-effectiveness analysis. A pharmacoeconomic decision model was developed to simulate 3-week patients transition in 20-year time horizon to access the cost-effectiveness of three competing first-line treatments among ITH-testing directed toripalimab plus chemotherapy, toripalimab plus chemotherapy, and chemotherapy alone. Survival data were obtained from EXTENTORCH trial, cost and utility values were gathered from the dataset and published studies, annual discount rate of 5% was used for cost and utility values. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. One-way and probabilistic sensitivity analyses were conducted to estimate the robustness of the model results. In base-case analysis, compared with toripalimab plus chemotherapy and chemotherapy alone, ITH-testing directed therapy could bring additional 0.14 QALYs and 0.29 QALYs, with marginal costs of $3750.75 and $7778.18, resulting in the ICER of $27,353.27/QALY and $26,461.46/QALY, respectively, which lower than the Chinese willingness-to-pay (WTP) threshold. Sensitivity analyses demonstrated the model results were robust, probabilistic sensitivity analyses showed the probability of ITH-testing directed therapy could be considered cost-effective was 61%. ITH-testing directed treatment was likely to be the most cost-effective first-line option compared with toripalimab plus chemotherapy and chemotherapy alone for patients with previously untreated ES-SCLC from the Chinese health-care system perspective.

Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.