Preoperative anemia and long-term survival in patients undergoing colorectal cancer surgery: a retrospective cohort study.

BACKGROUND: The impact of preoperative anemia on a survival outcome and the importance of correcting preoperative anemia in patients with colorectal cancer (CRC) remain controversial. This study aimed to explore how preoperative anemia affects the long-term survival of patients undergoing colorectal cancer surgery. METHODS: This was a retrospective cohort study in which adult patients underwent surgical resection for colorectal cancer between January 1, 2008, and December 31, 2014, at a large tertiary cancer center. A total of 7436 patients were enrolled in this study. Anemia was defined according to the diagnostic criteria of China (hemoglobin level < 110 g/L for women and < 120 g/L for men). The median follow-up time was 120.5 months (10.0 years). Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce selection bias. Overall survival (OS) and disease-free survival (DFS) were compared between patients with and without preoperative anemia using the Kaplan-Meier estimator and the weighted log-rank test based on IPTW. Univariate and multivariate Cox proportional hazards models were used to assess factors associated with OS and DFS. Multivariable Cox regression was also used to assess red blood cell (RBC) transfusion associations between preoperative anemia and outcomes. RESULTS: After IPTW adjustment, clinical profiles were similar, except that tumor location and TNM stage remained imbalanced between the preoperative anemia and preoperative non-anemia groups (p < 0.001). IPTW analysis showed that the 5-year OS rate (71.3 vs. 78.6%, p < 0.001) and the 5-year DFS rate (63.9 vs. 70.9%, p < 0.001) were significantly lower in the preoperative anemia group. Multivariate analysis showed that preoperative anemia was associated with poorer OS and DFS, while RBC transfusion may improve OS (hazard ratio [HR] 0.54, p = 0.054) and DFS (HR 0.50, p = 0.020) in CRC patients with preoperative anemia. CONCLUSIONS: Preoperative anemia is an independent risk factor for survival in patients undergoing colorectal surgery. Strategies to reduce preoperative anemia in patients with CRC should be considered.

EEG-derived pain threshold index for prediction of postoperative pain in patients undergoing laparoscopic urological surgery: a comparison with surgical pleth index.

Recently a novel pain recognition indicator derived from electroencephalogram(EEG) signals, pain threshold index(PTI) has been developed. The aim of this study was to determine whether PTI can be used for prediction of postoperative acute pain while surgical pleth index(SPI) applied as control. Eighty patients undergoing laparoscopic urological surgery under general anesthesia were enrolled. Data of SPI, PTI and a sedative index-wavelet index(WLI) were recorded within last 10 min at the end of surgery. The postoperative pain scores (NRS, numerical rating scale) were obtained. The Bland-Altman analysis was used for evaluation of consistency between PTI and SPI, whereas receiver-operating characteristic (ROC) curves was used for the mean values of PTI, SPI, and WLI to distinguish between mild (NRS 0-3) and moderate-severe (NRS 4-10) pain, and calculate their "best-fit" cut-off values. Data from 76 patients were included for final analysis. There was a good agreement between SPI and PTI values at the end of surgery. The ROC analysis showed a cut-off PTI value of 53 to discriminate between mild and moderate-to-severe pain, while SPI is 44 for this discrimination. Further analysis indicated that PTI had a best predictive accuracy reflected by highest area under curve (AUC)(0.772, 95% CI: 0.661-0.860)with sensitivity(62.50%) and specificity(90.91%) and a best positive predictive value(83.3%,95% CI: 68.4-98.2%). PTI obtained at the end of surgery, which have better predictive accuracy for postoperative pain than SPI, could differentiate the patients with moderate-to-severe pain from those with mild pain after they awaken from anesthesia.Clinical trial registration Chinese Clinical Trials Registry: ChiCTR1900024789.

Dexmedetomidine promotes colorectal cancer progression via Piwil2 signaling.

PURPOSE: α2-adrenoceptor agonist dexmedetomidine (DEX) has been reported to promote tumorigenesis. Stem-cell protein Piwil2 is associated with cancer progression. Whether Piwil2 plays a role in tumor-promoting effects of DEX is unknown. METHODS: We examined the expression of Piwil2 in human colorectal cancer (CRC) cell lines with/without DEX treatment. We also studied the roles of Piwil2 in proliferation, invasion, migration, as well as expressions of epithelial-mesenchymal transition (EMT)-related proteins in DEX-treated in vitro and in vivo CRC models. And the experiments with genetic and pharmacological treatments were conducted to investigate the underlying molecular mechanism. RESULTS: RNA-sequencing (RNA-seq) analysis found Piwil2 is one of most upregulated genes upon DEX treatment in CRC cells. Furthermore, Piwil2 protein levels significantly increased in DEX-treated CRC cancer cells, which promoted proliferation, invasion, and migration in both CRC cell lines and human tumor xenografts model. Mechanistically, DEX increased nuclear factor E2-related factor 2 (Nrf2) expression, which enhanced Piwil2 transcription via binding to its promoter. Furthermore, in vitro experiments with Piwil2 knockdown or Siah2 inhibition indicated that DEX promoted EMT process and tumorigenesis through Siah2/PHD3/HIF1α pathway. The experiments with another α2-adrenoceptor agonist Brimonidine and antagonists yohimbine and atipamezole also suggested the role of Piwil2 signaling in tumor-promoting effects via an α2 adrenoceptor-dependent manner. CONCLUSION: DEX promotes CRC progression may via activating α2 adrenoceptor-dependent Nrf2/Piwil2/Siah2 pathway and thus EMT process. Our work provides a novel insight into the mechanism underlying tumor-promoting effects of α2-adrenoceptor agonists.

CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model.

The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C-C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1ß, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.

Methylene blue targets PHD3 expression in murine microglia to mitigate lipopolysaccharide-induced neuroinflammation and neurocognitive impairments.

Methylene blue (MB) has anti-inflammatory properties, however, its underlying molecular mechanism remains elusive. This study aimed to investigate whether and how MB could attenuate lipopolysaccharide (LPS)-induced microglial activation, neuroinflammation, and neurobehavioral deficits. We measured the expression of pro-inflammatory factors and performed three neurobehavioral tests to assess the effect of MB on neuroinflammation and neurocognitive dysfunction in LPS-treated adult C57BL/6N male mice or LPS-stimulated microglia cells. In vitro and in vivo experiments were further performed to investigate the molecular mechanism underlying MB inhibition of neuroinflammation using various experimental methods, including western blot, RT-qPCR, immunofluorescence, seahorse measurement, positron emission tomography (PET) scan, and flow cytometry analyses. Our results demonstrated that microglial activation and M1 polarization were induced by LPS exposure, resulting in an inflammatory response and neuronal apoptosis. Furthermore, LPS induced metabolic reprogramming in microglial cells. However, MB treatment substantially inhibited LPS-induced elevated levels of pro-inflammatory factors and reversed metabolic activation in vivo, which eventually led to the resolution of neuroinflammation and neurobehavioral improvement. Mechanistically, MB specifically inhibited the LPS-induced overexpression of PHD3 in vitro and in vivo. The pharmacological and genetic manipulations unveiled that the Siah2/Morg1/PHD3 signaling pathway may mediate MB protection against LPS-induced neuroinflammation and neurotoxicity. Therefore MB inhibited PHD3-dependent neuroinflammation may via Siah2/Morg1/PHD3 pathway, and that PHD3 expressed in microglia may be a drug target for the treatment of neuroinflammation-related brain disorders.

Inhibition or Deletion of Hydroxylases-Prolyl-4-Hydroxyases 3 Alleviates Lipopolysaccharide-induced Neuroinflammation and Neurobehavioral Deficiency.

It is well known that neuroinflammation plays a key role in neurodegenerative diseases. Hypoxia-inducible factor (HIF) and its hydroxylases-Prolyl-4-hydroxyases (PHDs) have been found to modulate the inflammatory processes. Here, the effects of PHDs enzyme onlipopolysaccharide-induced neuroinflammation and neurocognitive deficits were investigated. BV2 microglia cells were stimulated by LPS (1 µg/ml) as neuroinflammation model in vitro. Dimethyloxalylglycine (DMOG, 100 µM) and PHD3-siRNA were used to suppress the expression of PHD3. In vivo, mice received consecutive intraperitoneal injection of LPS (500 µg/kg) for 7 days, and intraperitoneal injection of DMOG (100 mg/kg) was applied 1 h before LPS at the same days. Several neurobehavioral tests (Open field, Novel object recognition and Morris water maze) were used to measure cognitive function. RT-qPCR and Western blotting were used to investigate the expression of inflammatory cytokines, HIF-PHDs protein. Metabolic reprogramming was measured by seahorse method. The results revealed that LPS induced neuroinflammation and PHD3 expression in vivo and vitro. DMOG and PHD3knockout decreased expression of inflammatory cytokines and improved the metabolic reprogramming caused by LPS treatment. Furthermore, pretreatment of DMOG reversed learning and memory deficits in systemic LPS-exposed mice through anti-neuroinflammation, which is independent of DMOG angiogenesis. These findings suggested that PHD3 may mediate LPS-induced microglial activation and neuroinflammation-associated neurobehavioral deficits.

Methylene blue reduces incidence of early postoperative cognitive disorders in elderly patients undergoing major non-cardiac surgery: An open-label randomized controlled clinical trial.

STUDY OBJECTIVE: The purpose of the present study was to investigate whether methylene blue (MB) could reduce the incidences of postoperative delirium (POD) and early postoperative cognitive dysfunction (POCD) in elderly patients undergoing major non-cardiac surgery. DESIGN: Prospective, randomized, open-label clinical trial. SETTING: University-affiliated hospital. PATIENTS: Two hundred and forty-eight elderly patients scheduled for non-cardiac surgery. INTERVENTIONS: Elderly patients undergoing non-cardiac major surgery were randomly assigned to MB group (n = 124), who receiving intravenous infusion of 2 mg/kg MB within 60 min immediately after anesthetic induction, or control group (n = 124), who receiving equal volume saline in the same way. MEASUREMENTS: All patients were evaluated with delirium and neuropsychological batteries before and after surgery, as well as perioperative adverse events. Two plasma biomarkers superoxide dismutase (SOD) and homocysteine (HCY) were measured pre- and post-operatively. MAIN RESULTS: There were total 39 cases(15.7%)experienced POD. The incidence of POD in MB group was significantly less than that in control group (7.3% vs. 24.2%, OR = 0.24, 95%CI: 0.11-0.53, p < 0.001). The incidence of early POCD at postoperative 7th day in MB group was also less than that in control group (16.1% vs. 40.2%, OR = 0.30, 95% CI: 0.16-0.57, p < 0.001). The adverse events were comparable in both groups. In addition, there was no significant correlation between POD/POCD and levels of SOD or HCY. CONCLUSION: We conclude that intraoperative intravenous 2 mg/kg MB could significantly reduce the incidences of POD and early POCD in elderly surgical patients, while not remarkably increase incidence of perioperative adverse events, suggesting MB may be clinically effective and safe for prevention of early postoperative neurocognitive disorders.