A potential immunotherapy target for breast cancer: parenchymal and immune-stromal expression of the NLRP3 inflammasome pathway.

BACKGROUND: The NOD-, LRR- and pyrin domain­containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial. METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (ASC), IL-1ß, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan-Meier survival curves, and Cox regression analysis. RESULTS: In the parenchymal cells, ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan-Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis. CONCLUSIONS: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target. TRIAL REGISTRATION: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910).

Cellular Evidence for Telocytes Mediating Electroacupuncture to Ameliorate Obesity in Mice.

Electroacupuncture has been generally applied to target obesity, the principle of which is based on the meridian in traditional Chinese medicine. Although Telocytes (TCs) have been reported as the potential essence of meridians, their specific role in the electroacupuncture treatment of obesity remains unclear. Thus, we investigated the cellular evidence for TC-mediated electroacupuncture to alleviate obesity. Mice were divided into three groups as follows: electroacupuncture group (EA), control group (CG), and normal group (NG). The present study showed that the weight of perirenal white adipose tissue (rWAT), the serum level of total cholesterol, and the low-density lipoprotein cholesterol were all significantly decreased after electroacupuncture. Ultrastructurally, the prolongations (telopodes, Tps) of TCs were in direct contact with adipocytes, and lipid droplets were distributed on the surface of Tps. The proportions of double-positive fluorescent areas of TCs (CD34 and PDGFRα) were significantly elevated with concomitant elongated Tps in EA mice, as compared to those in CG mice. The expression of Cx43 and CD63 (gap junction and exosome markers) was significantly enhanced. These characteristics facilitated the transmission of electroacupuncture stimulation from skin to rWAT. We conclude that electroacupuncture relieved obesity by activating TCs morphologically, upregulating the gap junctions between TCs, and increasing the exosomes around TCs.

Effects of dezocine on morphine tolerance and opioid receptor expression in a rat model of bone cancer pain.

BACKGROUND: Clinically, the coadministration of opioids to enhance antinociception and decrease tolerance has attracted increasing research attention. We investigated the effects of dezocine, a mu- and kappa-opioid receptor agonist/antagonist, on morphine tolerance and explored the involvement of opioid receptor expression in a rat model of bone cancer pain. METHODS: Thermal nociceptive thresholds were measured after the subcutaneous injection of morphine (10 mg/kg) alone or combined with dezocine (10 or 1 mg/kg) for 7 consecutive days. Real-time PCR and western blot analysis were used to examine opioid receptor expression in the periaqueductal gray (PAG) and spinal cord. RESULTS: The analgesic effect was significantly decreased after 4 days of morphine administration. We observed that low-dose dezocine significantly attenuated morphine tolerance without reducing the analgesic effect of morphine. Low-dose dezocine coadministration significantly reversed the downregulated expression of mu (MOR) and delta (DOR) opioid receptors in the PAG and the upregulated expression of kappa (KOR) and DOR in the spinal cord induced by morphine. Moreover, low-dose dezocine coadministered with morphine significantly inhibited KOR expression in both the PAG and spinal cord. CONCLUSIONS: The combination of low-dose dezocine with morphine may prevent or delay the development of morphine tolerance in a rat model of bone cancer pain. The regulation of opioid receptor expression in the PAG and spinal cord may be part of the mechanism.

Long-term endoscopic submucosal dissection with postoperative lung injury: a case report.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been recognized as a safe and minimally invasive technique for the removal of early gastric cancer. Here, we describe a case of extended-duration ESD for a gastric tumor associated with intraoperative perforation and bleeding. Unfortunately, the patient developed acute lung injury (ALI) after the operation. CASE PRESENTATION: A 72-year-old woman received ESD for a gastric tumor under general anesthesia. Preoperatively, endoscopic ultrasonography (EUS) showed a 3.1 × 3.5 cm hypoechoic, well-defined mass at the junction of the antrum and body of the stomach on the greater curvature, originating in the muscularis propria layer. During the ESD procedure, when the submucosal mass was stripped, it was found to be closely adhered to the muscular layer and serosa layer, and a full-thickness incision was performed. The abdominal cavity was gradually filled with carbon dioxide gas, and abdominal puncture was performed to reduce intra-abdominal hypertension (IAH). Because the mass adhered to the greater omentum and there was more bleeding during the operation, a long duration of hemostasis and suturing of the wound was required. The whole operation lasted nearly 9 h, and total blood loss was 800 ml. After surgery, acute lung injury was suspected, and the patient was sent to the intensive care unit (ICU) for further treatment. CONCLUSIONS: The operation time of ESD and IAH caused by perforation are closely related to a poor prognosis. We should pay attention to the impact of operation time on patients and improve awareness regarding protecting important organ functions.

Risk Factors and Prognosis of Perioperative Atrial Fibrillation in Elderly Patients Undergoing VATS Lung Surgery: A Retrospective Cohort Study.

Background: Atrial fibrillation (AF) has become the most common postoperative arrhythmia of thoracic surgery. This study aimed to investigate the risk factors and complications of perioperative atrial fibrillation (PoAF) in elderly patients who underwent video-assisted thoracoscopic surgery (VATS). Methods: Data were collected from patients who underwent VATS between January 2013 and December 2022 at Peking Union Medical College Hospital (PUMCH). Univariable analyses and multivariable logistic regression analyses were used to determine the factors correlated with PoAF. Receiver operating characteristic (ROC) curve was used to evaluate the discrimination of the indicators to predict PoAF. Results: The study enrolled 2920 patients, with a PoAF incidence of 5.2% (95% CI 4.4%-6.0%). In the logistic regression analyses, male sex (OR=1.496, 95% CI 1.056-2.129, P=0.024), left atrial anteroposterior dimension (LAD) ≥40 mm (OR=2.154, 95% CI 1.235-3.578, P=0.004), hypertension (HTN) without regular treatment (OR=2.044, 95% CI 0.961-3.921, P=0.044), a history of hyperthyroidism (OR=4.443, 95% CI 0.947-15.306, P=0.030), surgery of the left upper lobe (compared to other lung lobes) (OR=1.625, 95% CI 1.139-2.297, P=0.007), postoperative high blood glucose (BG) (OR=2.482, 95% CI 0.912-5.688, P=0.048), and the time of chest tube removal (per day postoperatively) (OR=1.116, 95% CI 1.038-1.195, P=0.002) were found to be significantly associated with PoAF. The area under the ROC curve was 0.707 (95% CI 0.519-0.799). 86.9% patients were successfully converted to sinus rhythm. Compared with the non-PoAF group, the PoAF group had significantly greater risks of prolonged air leakage, postoperative acute coronary syndrome, longer ICU stays, and longer hospital stays. Conclusion: Male sex, LAD≥40 mm, HTN without regular treatment, a history of hyperthyroidism, surgery of the left upper lobe, postoperative BG, and the time of chest tube removal were associated with PoAF. These findings may help clinicians identify high-risk patients and take preventive measures to minimize the incidence and adverse prognosis of PoAF.

The incidence and risk factors of perioperative cardiac complications in noncardiac major surgery in high-altitude areas: A prospective trial in Tibet autonomous region, China.

Background: The risk of perioperative cardiac complications (PCCs) in patients living in high-altitude areas may increase with more adverse clinical outcomes due to the special geographical environment, which has not yet been studied. We aimed to determine the incidence and analyze risk factors for PCCs in adult patients undergoing major noncardiac surgery in the Tibet Autonomous Region. Methods: This prospective cohort study enrolled resident patients from high-altitude areas receiving major noncardiac surgery in Tibet Autonomous Region People's Hospital in China. Perioperative clinical data were collected, and the patients were followed up until 30 days after surgery. The primary outcome was PCCs during the operation and within 30 days after the surgery. Logistic regression was used to build the prediction models for PCCs. A receiver operating characteristic (ROC) curve was used to evaluate the discrimination. A prognostic nomogram was constructed to generate a numerical probability of PCCs for patients undergoing noncardiac surgery in high-altitude areas. Results: Among the 196 patients living in high-altitude areas involved in this study, 33 (16.8%) suffered PCCs perioperatively and within 30 days after surgery. Eight clinical factors were identified in the prediction model, including older age (P = 0.028), extremely high altitude above 4,000 m (P = 0.442), preoperative metabolic equivalent (MET) < 4 (P = 0.153), history of angina within 6 months (P = 0.037), history of great vascular disease (P = 0.073), increased preoperative high sensitivity C-reactive protein (hs-CRP) (P = 0.072), intraoperative hypoxemia (P = 0.025) and operation time >3 h (P = 0.043). The area under the curve (AUC) was 0.766 (95% confidence interval: 0.785-0.697). The score calculated from the prognostic nomogram predicted the risk of PCCs in high-altitude areas. Conclusion: The incidence of PCCs in resident patients living in high-altitude areas who underwent noncardiac surgery was high, and the risk factors included older age, high altitude above 4,000 m, preoperative MET < 4, history of angina within 6 months, history of great vascular disease, increased preoperative hs-CRP, intraoperative hypoxemia, and operation time >3 h. The prognostic nomogram of this study could help to assess the PCCs for patients in high-attitude areas undergoing noncardiac surgery. Clinical Trial Registration: ClinicalTrials.gov ID: NCT04819698.

Efficacy and safety of ciprofol versus propofol for the induction of anesthesia in adult patients: a multicenter phase 2a clinical trial.

BACKGROUND: Ciprofol is a novel 2, 6-disubstituted phenolic derivative anesthetic that binds to the gamma-aminobutyric acid-A receptor. AIM: To determine the equally potent dose of ciprofol compared with propofol as an induction agent for general anesthesia in patients undergoing selective surgery, and to assess its safety. METHOD: A total of 109 patients undergoing selective non-emergency, non-cardiothoracic or non-neurosurgical surgery requiring tracheal intubation for general anesthesia were enrolled. Ten patients per group were assigned to ciprofol-0.3, 0.4 and 0.5 mg/kg, and propofol-2.0 or 2.5 mg/kg groups, respectively to receive an intravenous bolus dose. An additional 20 patients were enrolled in the ciprofol-0.3, 0.5 or propofol-2.0 mg/kg groups. The primary outcome was the success rate of induction defined as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) ≤ 1 after the initial bolus dose. The secondary outcomes included the time to reach MOAA/S ≤ 1, the time to loss of the eyelash reflex, the incidences and severity of adverse events (AEs). RESULTS: The success rates were 100% for all 5 groups. The mean time to MOAA/S ≤ 1 and the time to loss of the eyelash reflex were not different among the 5 groups, regardless of whether a top-up dose was needed. There were no significant differences in the incidences and severity of AEs in the dose ranges investigated of ciprofol vs. propofol. CONCLUSION: The efficacy and safety of a single bolus dose of ciprofol-0.5 mg/kg for the general anesthesia induction in selective surgery patients was comparable to that of propofol-2.0 mg/kg. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03698617, retrospectively registered.

Effect of Anesthesia/Surgery on Gut Microbiota and Fecal Metabolites and Their Relationship With Cognitive Dysfunction.

Aims: Post-operative cognitive dysfunction (POCD) is the decline in cognitive function of the central nervous system (CNS) after anesthesia/surgery. The present study explored whether anesthesia/surgery altered gut microbiota and fecal metabolites, examining their associations with risk factors of cognitive dysfunction in aged mice. Methods: Sixteen-month-old C57BL/6 mice underwent abdominal surgery under isoflurane anesthesia to establish an animal model of POCD. The Morris water maze test (MWMT) was used as an indicator of memory after surgery. The effects of anesthesia/surgical interventions on gut microbiota, fecal metabolites, hippocampus, and serum levels of inflammatory factors were examined. Results: The anesthesia/surgery induced more serious POCD behavior, increasing brain interleukin (IL)-6, and IL-1ß levels than sham control mice. The relative abundance of bacterial genera Bacteroidales_unclassified, Mucispirillum, and Clostridiales_unclassified declined, whereas that of Escherichia-Shigella, actinomyces, Ruminococcus_gnavus_group, and Lachnospiraceae_FCS020_group were enriched after anesthesia/surgery compared to the baseline controls. Liquid chromatography-mass spectrometry (LC-MS) showed that the metabolites differed between post-anesthesia+surgery (post_A + S) and baseline samples and were associated with the fecal metabolism of tryptophan, kynurenic acid, N-oleoyl γ-aminobutyric acid (GABA), 2-indolecarboxylic acid, and glutamic acid. Furthermore, the differential metabolites were associated with alterations in the abundance of specific bacteria. These results indicate that the POCD intervention may be achieved by targeting specific bacteria associated with neurotransmitter metabolism. Conclusions: A transient cognitive disturbance induced by anesthesia/surgery may be associated with unfavorable alterations in gut microbiota and fecal metabolites, thereby contributing to the POCD development.

Donepezil attenuates the development of morphine tolerance in rats with cancer-induced bone pain: The role of cortical N-methyl-D-aspartate receptors.

Cancer-induced bone pain (CIBP), which is associated with poor quality of life, is most commonly treated using opioids. However, long-term use of morphine for analgesia induces tolerance and can diminish the treatment's effectiveness. The mechanisms that underlie morphine tolerance have been reported to be related to the inflammation of the nervous system and hyperactivation of N-methyl-D-aspartate receptors (NMDARs). Donepezil is an anti-inflammatory and neuroprotective drug that is thought to alleviate morphine tolerance. In this study, we aimed to investigate the effect of three different dosages of donepezil (1, 1.5 and 2 mg/kg) on morphine tolerance in rats with CIBP, and the possible involvement of donepezil-mediated NMDAR subunit 1 (NR1). We found that donepezil can prolong the analgesic efficacy of morphine and delay the development of chronic morphine tolerance. Furthermore, continuous morphine injection increased the expression of NR1, and this was suppressed by co-administration with donepezil using both western blotting and immunofluorescence. Our findings demonstrate that donepezil has the potential to attenuate morphine tolerance, possibly by inhibiting NR1 activity in the cortex.

Donepezil prevents morphine tolerance by regulating N-methyl-d-aspartate receptor, protein kinase C and CaM-dependent kinase II expression in rats.

Current studies have indicated that donepezil as a cholinesterase inhibitor can attenuate morphine-induced tolerance. The present study aimed to evaluate the possible role of N-methyl-d-aspartate receptors (NMDARs), protein kinase C (PKC) and CaM-dependent kinase II (CaMKII) pathways in this effect. Female Wistar rats received daily morphine (10 mg/kg, i.p.) alone or in combination with donepezil (1.5 or 2 mg/kg, gavaged) for 14 days. The analgesic effect was assessed by Von-frey, hotplate and tail flick test. On the 15th day, the periaqueductal gray (PAG) and lumbar spinal cord of rats were dissected. Then, protein levels of NMDAR-NR1, NR2B, PKCγ and CaMKIIα were tested using Western blot method. The results showed that morphine tolerance was seen after 8-10 days of injection compared with control group, while daily co-administration of donepezil with morphine prolonged the occurrence of analgesic tolerance. Western blot showed that morphine significantly increased NR1, PKCγ and CaMKIIα expressions in PAG, and significantly increased PKCγ and CaMKIIα in spinal cord. In contrast, donepezil downregulated NR1 and PKCγ in PAG, and downregulated PKCγ and CaMKIIα in spinal cord. Moreover, donepezil alone activates NR1 and NR2B in spinal cord, which needs to be further studied. Thus, the present results suggest that the attenuation effects of donepezil on morphine tolerance are possibly mediated by preventing morphine-induced upregulations in NR1, PKCγ and CaMKIIα expressions.

Comparison of nalbuphine and sufentanil for colonoscopy: A randomized controlled trial.

OBJECTIVES: Nalbuphine is as effective as morphine as a perioperative analgesic but has not been compared directly with sufentanil in clinical trials. The aims of this study were to compare the efficacy and safety of nalbuphine with that of sufentanil in patients undergoing colonoscopy and to determine the optimal doses of nalbuphine in this indication. METHODS: Two hundred and forty consecutive eligible patients aged 18-65 years with an American Society of Anesthesiologists classification of I-II and scheduled for colonoscopy were randomly allocated to receive sufentanil 0.1 µg/kg (group S), nalbuphine 0.1 mg/kg (group N1), nalbuphine 0.15 mg/kg (group N2), or nalbuphine 0.2 mg/kg (group N3). Baseline vital signs were recorded before the procedure. The four groups were monitored for propofol sedation using the bispectral index, and pain relief was assessed using the Visual Analog Scale and the modified Behavioral Pain Scale for non-intubated patients. The incidences of respiratory depression during endoscopy, nausea, vomiting, drowsiness, and abdominal distention were recorded in the post anesthesia care unit and in the first and second 24-hour periods after colonoscopy. RESULTS: There was no significant difference in analgesia between the sufentanil group and the nalbuphine groups (p>0.05). Respiratory depression was significantly more common in group S than in groups N1 and N2 (p<0.05). The incidence of nausea was significantly higher in the nalbuphine groups than in the sufentanil group in the first 24 hours after colonoscopy (p<0.05). CONCLUSIONS: Nalbuphine can be considered as a reasonable alternative to sufentanil in patients undergoing colonoscopy. Doses in the range of 0.1-0.2 mg/kg are recommended. The decreased risks of respiratory depression and apnea make nalbuphine suitable for patients with respiratory problems.