Opioid−free anesthesia attenuates perioperative immunosuppression by regulating macrophages polarization in gastric cancer patients treated with neoadjuvant PD-1 inhibitor

BackgroundOpioid anesthesia can modulate the impaired immune response and opioid-sparing anesthesia may preserve immune functions. This study was performed to assess the effects of opioid-free anesthesia (OFA) and opioid-based anesthesia (OA) on perioperative macrophages differentiation, cytokine changes, and perioperative complications in locally advanced GC (LAGC) patients.MethodsWe used quality of recovery-15 (QoR-15) questionnaire scores and visual analog scale (VAS) scores to compare postoperative quality of recovery and pain level. In addition, the adverse reactions of patients in the two groups were compared. The perioperative serum level of inflammatory cytokines and the ratio of macrophage subtypes were detected.ResultsThe OFA group had significantly longer extubation time and PACU stay, whereas the OA group had significantly higher rate of hypotension, higher doses of norepinephrine, higher PONV and dizziness rate, and delayed flatus passage time. The QoR-15 score on postoperative 24 h was significantly higher in OFA group than in OA group. At the end of or after the surgery, the OFA group had higher levels of interleukin (IL)-12, IL-1β, tumor necrosis factor (TNF)-α, CD68+CD163− macrophage rate, but lower levels of IL-10, transforming growth factor (TGF)-β, and CD68+CD163+ macrophage rate, indicating OFA attenuated perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization. And the reversal tendency is more obvious in LAGC patients with neoadjuvant PD-1 inhibitor.ConclusionsThe OFA may attenuate perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization in LAGC patients with neoadjuvant PD-1 inhibitor.Clinical trial registrationhttp://gcpgl.sysucc.org.cn, identifier 2022-FXY-001

Effect of Dexmedetomidine-Assisted Intravenous Anesthesia on Gastrointestinal Motility in Colon Cancer Patients After Open Colectomy

BackgroundTo explore the effect of dexmedetomidine (Dex)-assisted intravenous anesthesia on gastrointestinal motility in patients with colon cancer (CC) after open colectomy.MethodsA total of 102 patients with CC, undergoing open colectomy in our hospital from January 2018 to January 2020, were selected and randomly divided into an observation group (n = 51) and a control group (n = 51). The patients in the control group received a routine combination of intravenous and inhalation anesthesia (CIIA), while those in the observation group received a Dex-assisted CIIA. The systolic blood pressure (SBP), the diastolic blood pressure (DBP), heart rate (HR), and the mean arterial pressure (MAP) were compared at different time points between the two groups. In addition, the intraoperative general conditions, the dosage of anesthetics, and the recovery of gastrointestinal functions were also compared between the two groups. Moreover, before operation and at 24 h after operation, the levels of serum gastrin (GAS) and plasma motilin (MTL) were detected by radioimmunoassay, and the level of plasma cholecystokinin (CCK) was detected by an enzyme-linked immunosorbent assay. The incidence of gastrointestinal complications was recorded in both groups.ResultsAt T1-T3, the HR, SBP, DBP, and MAP levels were lower in both groups than those at T0. In addition, they were also lower in the observation group than those in the control group, showing significant differences (p &amp;lt; 0.05). The dosage of propofol and remifentanil in the observation group was lower than that in the control group, and there was a significant difference (p &amp;lt; 0.05). In the observation group, the postoperative first exhaust time, first defecation time, first ambulation time, and first feeding time were all earlier than those in the control group with significant differences (p &amp;lt; 0.05). After the operation, the observation group had higher levels of GAS and MTL but a lower level of CCK than the control group, and the differences were significant (p &amp;lt; 0.05). The incidence rate of gastrointestinal complications in the observation group (7.04%) was lower than that in the control group (19.61%), and there was a significant difference (χ2 = 4.346, p &amp;lt; 0.05).ConclusionsDex-assisted intravenous anesthesia can facilitate the recovery of gastrointestinal motility, can regulate the levels of gastrointestinal hormones, and can stabilize the levels of hemodynamic indexes in patients with CC after open colectomy.</jats:sec

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Glioblastoma multiform is a lethal primary brain tumor derived from astrocytic, with a poor prognosis in adults. Reticulocalbin-1 (RCN1) is a calcium-binding protein, dysregulation of which contributes to tumorigenesis and progression in various cancers. The present study aimed to identify the impact of RCN1 on the outcomes of patients with Glioblastoma multiforme (GBM). The study applied two public databases to require RNA sequencing data of Glioblastoma multiform samples with clinical data for the construction of a training set and a validation set, respectively. We used bioinformatic analyses to determine that RCN1 could be an independent factor for the overall survival of Glioblastoma multiform patients. In the training set, the study constructed a predictive prognostic model based on the combination of RCN1 with various clinical parameters for overall survival at 0.5-, 1.0-, and 1.5-years, as well as developed a nomogram, which was further validated by validation set. Pathways analyses indicated that RCN1 was involved in KEAS and MYC pathways and apoptosis. In vitro experiments indicated that RCN1 promoted cell invasion of Glioblastoma multiform cells. These results illustrated the prognostic role of RCN1 for overall survival in Glioblastoma multiform patients, indicated the promotion of RCN1 in cell invasion, and suggested the probability of RCN1 as a potential targeted molecule for treatment in Glioblastoma multiform.</jats:p

Image1_Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme.TIF

Glioblastoma multiform is a lethal primary brain tumor derived from astrocytic, with a poor prognosis in adults. Reticulocalbin-1 (RCN1) is a calcium-binding protein, dysregulation of which contributes to tumorigenesis and progression in various cancers. The present study aimed to identify the impact of RCN1 on the outcomes of patients with Glioblastoma multiforme (GBM). The study applied two public databases to require RNA sequencing data of Glioblastoma multiform samples with clinical data for the construction of a training set and a validation set, respectively. We used bioinformatic analyses to determine that RCN1 could be an independent factor for the overall survival of Glioblastoma multiform patients. In the training set, the study constructed a predictive prognostic model based on the combination of RCN1 with various clinical parameters for overall survival at 0.5-, 1.0-, and 1.5-years, as well as developed a nomogram, which was further validated by validation set. Pathways analyses indicated that RCN1 was involved in KEAS and MYC pathways and apoptosis. In vitro experiments indicated that RCN1 promoted cell invasion of Glioblastoma multiform cells. These results illustrated the prognostic role of RCN1 for overall survival in Glioblastoma multiform patients, indicated the promotion of RCN1 in cell invasion, and suggested the probability of RCN1 as a potential targeted molecule for treatment in Glioblastoma multiform.</p

Selective activation of AKAP150/TRPV1 in ventrolateral periaqueductal gray GABAergic neurons facilitates conditioned place aversion in male mice

Abstract Aversion refers to feelings of strong dislike or avoidance toward particular stimuli or situations. Aversion can be caused by pain stimuli and has a long-term negative impact on physical and mental health. Aversion can also be caused by drug abuse withdrawal, resulting in people with substance use disorder to relapse. However, the mechanisms underlying aversion remain unclear. The ventrolateral periaqueductal gray (vlPAG) is considered to play a key role in aversive behavior. Our study showed that inhibition of vlPAG GABAergic neurons significantly attenuated the conditioned place aversion (CPA) induced by hindpaw pain pinch or naloxone-precipitated morphine withdrawal. However, activating or inhibiting glutamatergic neurons, or activating GABAergic neurons cannot affect or alter CPA response. AKAP150 protein expression and phosphorylated TRPV1 (p-TRPV1) were significantly upregulated in these two CPA models. In AKAP150flox/flox mice and C57/B6J wild-type mice, cell-type-selective inhibition of AKAP150 in GABAergic neurons in the vlPAG attenuated aversion. However, downregulating AKAP150 in glutamatergic neurons did not attenuate aversion. Knockdown of AKAP150 in GABAergic neurons effectively reversed the p-TRPV1 upregulation in these two CPA models utilized in our study. Collectively, inhibition of the AKAP150/p-TRPV1 pathway in GABAergic neurons in the vlPAG may be considered a potential therapeutic target for the CPA response

Probabilistic Diffusion Models Advance Extreme Flood Forecasting

Abstract Extreme floods pose escalating risks in a changing climate, yet forecasting remains challenging due to peak flow underestimation and high uncertainty. We introduce diffusion‐based runoff model (DRUM), a probabilistic deep learning (DL) approach that advances extreme flood forecasting across representative basins in the contiguous United States. DRUM outperforms state‐of‐the‐art benchmarks, enhancing nowcasting skill for the top 1‰ of flows in 72.3% of studied basins. Under operational scenarios, DRUM extends reliable lead times by nearly a full day for 20‐ and 50‐year floods. When evaluated with measured precipitation, an ideal condition, recall improves by 0.3–0.4 and the early warning window extends by 2.3 days for 50‐year floods. The enhancement potential varies regionally, with precipitation‐driven flood zones in the eastern and northwestern US benefiting most, gaining 3–7 days in lead time. These findings highlight the transformative potential of diffusion models as a cutting‐edge generative AI technique for advancing hydrology and broader Earth system sciences

Patients with Asian-type DEL can safely be transfused using RhD-positive blood

Red blood cells (RBCs) of the Asian-type DEL phenotype express few RhD proteins and are typed as serologic RhD-negative (D-) in routine testing. RhD-positive (D+) RBC transfusion for Asian-type DEL patients has been proposed but has not been generally adopted due to a lack of direct evidence regarding its safety and underlying mechanism. We performed a single-arm multicenter clinical trial to document the outcome of D+ RBC transfusion in Asian-type DEL patients; none of the recipients (0/42; 95% confidence interval, 0%-8.40%) developed alloanti-D after a median follow-up of 226 days. We conducted a large retrospective study to detect alloanti-D immunization in 4,045 serologic D- pregnant women throughout China; alloanti-D was found only in true D- individuals (2.63%, 79/3,009), but not in those with Asian-type DEL (0/1,032). We further retrospectively examined 127 serologic D- pregnant women who had developed alloanti-D and found none with Asian-type DEL (0/127). Finally, we analyzed RHD transcripts from Asian-type DEL erythroblasts and examined antigen epitopes expressed by various RHD transcripts in vitro, finding a low abundance of full-length RHD transcripts (0.18% of the total) expressing RhD antigens carrying the entire repertoire of epitopes, which could explain the immune tolerance against D+ RBCs. Our results provide multiple lines of evidence that individuals with Asian-type DEL cannot produce alloanti-D when exposed to D+ RBCs following transfusion or pregnancy. Therefore, we recommend considering D+ RBC transfusion and discontinuing anti-D prophylaxis in Asian-type DEL patients, including pregnant women. This clinical trial is registered at www.clinicaltrials.gov as NCT03727230