Effect of intraoperative low vs. conventional tidal volume on the incidence of postoperative acute kidney injury after noncardiac surgery: a two-center randomized clinical trial.

BACKGROUND: In adults undergoing noncardiac surgery, the correlation between intraoperative tidal volume and postoperative acute kidney injury (AKI) is unclear. This study aimed to investigate the effects of low tidal volume ventilation on the incidence of postoperative AKI compared with conventional tidal volume in adults undergoing noncardiac surgery. METHODS: This was a two-center prospective randomized controlled trial on adult patients who underwent noncardiac surgery and had a mechanical ventilation of >60 min. Patients were randomized to receive either a tidal volume of 6 mL/kg pre-predicted body weight (PBW, low tidal volume) or a tidal volume of 10 mL/kg pre-predicted body weight (conventional tidal volume). The primary outcome was the incidence of AKI after non-cardiac surgery. Appropriate statistical methods were used for this study. RESULTS: Among the 1982 randomized patients, 943 with low tidal volume and 958 with conventional tidal volume were evaluable for the primary outcome. Postoperative AKI occurred in 12 patients (1.3%) in the low tidal volume group and 11 patients (1.1%) in the conventional tidal volume group, with an odds ratio of 0.889 (95%CI, 0.391-2.03) and a relative risk of 0.999 ([95%CI, 0.989-1.01]; P=0.804). Postoperative serum creatinine levels increased in 284 (30.0%) patients with low tidal volume compared to 316 (32.0%) patients with conventional tidal volume (P=0.251). No difference in postoperative serum creatinine levels was found between the two groups (57.5 [49.0-68.2] µmol/L vs. 58.8[50.4-69.5] µmol/L, P=0.056). CONCLUSIONS: Among adults undergoing noncardiac surgery, low tidal volume mechanical ventilation did not significantly reduce the incidence of postoperative AKI compared with conventional tidal volume.

IL-6 secretion of CD4+ T cells stimulated by LC3-positive extracellular vesicles in human epithelial ovarian cancer.

BACKGROUND: Ovarian cancer (OC) as the most fatal gynecological malignancy worldwide, with epithelial ovarian cancer (EOC) being the predominant and most lethal form, poses a serious threat to human health. LC3-positive extracellular vesicles (LC3+ EVs) promote tumorigenesis by educating CD4+ T cells in a murine melanoma model. However, regulation of LC3+ EVs in human EOC remains largely unknown.  METHODS: Differential analysis of Rab8a, Hsp90α and Il6 expression was performed using GEPIA2. The number of LC3+ EVs and the frequency of Heat shock protein 90α+ LC3+ EVs (HSP90α+ LC3+ EVs) in the ascites of EOC patients were tested by flow cytometry. IL-6, IL-10, IFN-γ, IL-4 and TGF-ß were measured by ELISA. CD4+ T cells were isolated from peripheral blood of healthy human donors using MACS magnetic bead technology.  RESULTS: Higher Rab8a, Hsp90a and Il6 expression of cancer tissues compared with normal adjacent tissues in OC were found. The level of IL-6 was positively correlated with LC3+ EVs number, HSP90α+ LC3+ EVs percentage in the ascites, and ROMA index of the patient. In addition, elevated IL-6 production by CD4+ T cells induced by LC3+ EVs was observed, which was suppressed by anti-HSP90α or anti-TLR2.  CONCLUSIONS: LC3+ EVs level and HSP90α+ LC3+ EVs percentage were associated with elevated IL-6 in the ascites of EOC patients. HSP90α on LC3+ EVs from human EOC could stimulate CD4+ T cell production of IL-6 via TLR2.

Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis.

The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5'-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer. SIGNIFICANCE: Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.

Opioid-free anesthesia for postoperative recovery after video-assisted thoracic surgery: A prospective, randomized controlled trial.

Purpose: Opioid-based anesthesia is a traditional form of anesthesia that has a significant analgesic effect; however, it can cause nausea, vomiting, delirium, and other side effects. Opioid-free anesthesia with dexmedetomidine and lidocaine has attracted widespread attention. This study aimed to compare the effects of opioid-free and opioid-based anesthesia (OFA and OBA, respectively) on postoperative recovery in patients who had undergone video-assisted thoracic surgery. Methods: Eighty patients undergoing video-assisted thoracic surgery were assigned to receive either opioid-free anesthesia (OFA group) or opioid-based anesthesia (OBA group) according to random grouping. The primary outcome of the study was the quality of recovery-40 scores (QoR-40) 24 h postoperatively. The secondary outcome measure was numerical rating scale (NRS) scores at different times 48 h postoperatively. In addition to these measurements, other related parameters were recorded. Results: Patients who received opioid-free anesthesia had higher QoR-40 scores (169.1 ± 5.1 vs. 166.8 ± 4.4, p = 0.034), and the differences were mainly reflected in their comfort and emotional state; however, the difference between the two groups was less than the minimal clinically important difference of 6.3. We also found that the NRS scores were lower in the OFA group than in the OBA group at 0.5 h (both p < 0.05) and 1 h (both p < 0.05) postoperatively and the cumulative 0-24 h postoperative dosage of sufentanil in the OBA group was higher than that in the OFA group (p = 0.030). There were no significant differences in postoperative nausea and vomiting (PONV) (p = 0.159). No surgical or block complications were observed between the groups. Conclusion: Opioid-free analgesia potentially increased the postoperative recovery in patients who underwent video-assisted thoracic surgery. Trial registration: The study protocol was registered in the Chinese Clinical Trial Register under the number ChiCTR2100045344 (http://www.chictr.org.cn/showproj.aspx?proj=125033) on April 13, 2021.

Tumor cell-derived autophagosomes (DRibbles)-activated B cells induce specific naïve CD8+ T cell response and exhibit antitumor effect.

Dendritic cell (DC) vaccine has been proved to be an effective way in cancer immunotherapy in both preclinical and clinical studies. However, limitations in DC isolation and culture have hampered its practice and promoted the development of other antigen-presenting cells (APCs) sources to fulfill that role. Our previous studies have shown that B cells loaded by tumor cell-derived autophagosomes, which we named as DRibbles (defective ribosomal products-containing blebs), could reactivate DC-induced effector T cell response. In this study, the roles of DRibble-loaded B cells in priming naïve CD8+ T cell responses and controlling tumors were investigated. We found that high-mobility group box 1 protein (HMGB1) on DRibbles was involved in DRibble-induced B cell activation, and the DRibble-triggered B cell phagocytosis via the caveolae-mediated endocytosis pathway. By using OT-I mouse-derived T cells, we demonstrated that DRibble-loaded B cells could activate specific naïve CD8+ T cells in vitro and ex vivo. In a tumor-bearing mouse model, DRibble-loaded B cells elicited systemic antitumor immunity and significantly suppressed the tumor growth. Moreover, the antitumor efficacy of DRibble-loaded B cells was enhanced when they were combined with CpG and anti-CD40 stimulation. These results suggest that DRibble-loaded B cells represent a viable and practical therapeutic vaccination strategy that might have important clinical implications for tumor immunotherapy.