TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.

Mechanism through which the hsa-circ_0000992- hsa- miR- 936-AKT3 regulatory network promotes the PM2.5-induced inflammatory response in human bronchial epithelial cells.

BACKGROUND: Studies have shown that fine particulate matter (PM2.5) remains a significant problem in developing countries and plays a critical role in the onset and progression of respiratory illnesses. Circular RNAs (circRNAs) are involved in many pathophysiological processes,but their relationship to PM2.5 pollution is largely unexplored. OBJECTIVES: To elucidate the functional role of hsa_circ_0000992 in PM2.5-induced inflammation in a human bronchial epithelial cell line (16HBE) and to clarify whether the competing endogenous RNA (ceRNA) mechanism is involved in the interrelationships between hsa_circ_0000992 and hsa-miR-936 and the inflammatory signaling pathways. METHODS: Detection of inflammatory factors in 16HBE cells exposed to PM2.5 by RT-qPCR and ELISA.High throughput sequencing and bioinformatics analysis methods were used to screen circRNA.The bioinformatics analysis method western blotting and dual-luciferase reporter gene system were used to verify mechanisms associated with circRNA. RESULTS: PM2.5 cause inflammation in the 16HBE cells. High throughput sequencing and RT-qPCR result revealed that the expression of hsa_circ_0000992 was markedly up-regulated in 16HBE exposed to PM2.5. The binding sites between hsa_circ_0000992 and hsa-miR-936 was confirmed by dual-luciferase reporter gene system.Western blotting and RT-qPCR showed that hsa_circ_0000992 can interact with hsa-miR-936 to regulate AKT serine/threonine kinase 3(AKT3),thereby activating the PI3K/AKT pathway and ultimately promoting the expression of interleukin (IL)- 1ß and IL-8. CONCLUSION: PM2.5 can induce the inflammatory response in 16HBE cells by activating the PI3K/AKT pathway. The expression of hsa_circ_0000992 increased when PM2.5 stimulated 16HBE cells,and the circRNA could then regulate the inflammatory response.Hsa_circ_0000992 regulates the hsa-miR-936/AKT3 axis through the ceRNA mechanism,thereby activating the PI3K/AKT signaling pathway,increasing the expression of cellular inflammatory factors,and promoting PM2.5-induced respiratory inflammation.

Pancreatic ductal adenocarcinoma with synchronous and metachronous hepatic metastasis predicted by contrast-enhanced ultrasound.

Background: Contrast-enhanced ultrasound (CEUS) has proven valuable in diagnosing benign and malignant pancreatic diseases, but its value in evaluating hepatic metastasis remains to be further explored. This study investigated the relationship between CEUS features of pancreatic ductal adenocarcinoma (PDAC) and concomitant or recurrent liver metastases after treatment. Methods: This retrospective study included 133 participants with PDAC who were diagnosed with pancreatic lesions with CEUS at Peking Union Medical College Hospital from January 2017 to November 2020. According to the CEUS classification methods in our center, all the pancreatic lesions were classified as either with rich or poor blood supply. Additionally, quantitative ultrasonographic parameters were measured in the center and periphery of all pancreatic lesions. CEUS modes and parameters of the different hepatic metastasis groups were compared. The diagnostic performance of CEUS was calculated for diagnosing synchronous and metachronous hepatic metastasis. Results: The proportions of rich blood supply and poor blood supply were 46% (32/69) and 54% (37/69), respectively, in the no hepatic metastasis group; 42% (14/33) and 58% (19/33), respectively, in the metachronous hepatic metastasis (MHM) group; and 19% (6/31) and 81% (25/31), respectively, in the synchronous hepatic metastasis (SHM) group. The wash-in slope ratio (WIS ratio) between the center of the lesion and around the lesion and peak intensity ratio (PI ratio) between the center of the lesion and around the lesion had higher values in the negative hepatic metastasis group (P<0.05). In predicting synchronous and metachronous hepatic metastasis, the WIS ratio had the best diagnostic performance. The sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were 81.8%, 95.7%, 91.2%, 90.0%, and 91.7%, respectively, for MHM; and 87.1%, 95.7%, 93.0%, 90.0%, and 94.3%, respectively, for SHM. Conclusions: CEUS would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of PDAC.

Efficacy and safety of propofol target-controlled infusion combined with butorphanol for sedated colonoscopy.

BACKGROUND: Propofol is a short-acting, rapid-recovering anesthetic widely used in sedated colonoscopy for the early detection, diagnosis and treatment of colon diseases. However, the use of propofol alone may require high doses to achieve the induction of anesthesia in sedated colonoscopy, which has been associated with anesthesia-related adverse events (AEs), including hypoxemia, sinus bradycardia, and hypotension. Therefore, propofol co-administrated with other anesthetics has been proposed to reduce the required dose of propofol, enhance the efficacy, and improve the satisfaction of patients receiving colonoscopy under sedation. AIM: To evaluate the efficacy and safety of propofol target-controlled infusion (TCI) in combination with butorphanol for sedation during colonoscopy. METHODS: In this controlled clinical trial, a total of 106 patients, who were scheduled for sedated colonoscopy, were prospectively recruited and assigned into three groups to receive different doses of butorphanol before propofol TCI: Low-dose butorphanol group (5 µg/kg, group B1), high-dose butorphanol group (10 µg/kg, group B2), and control group (normal saline, group C). Anesthesia was achieved by propofol TCI. The primary outcome was the median effective concentration (EC50) of propofol TCI, which was measured using the up-and-down sequential method. The secondary outcomes included AEs in perianesthesia and recovery characteristics. RESULTS: The EC50 of propofol for TCI was 3.03 µg/mL [95% confidence interval (CI): 2.83-3.23 µg/mL] in group B2, 3.41 µg/mL (95%CI: 3.20-3.62 µg/mL) in group B1, and 4.05 µg/mL (95%CI: 3.78-4.34 µg/mL) in group C. The amount of propofol necessary for anesthesia was 132 mg [interquartile range (IQR), 125-144.75 mg] in group B2 and 142 mg (IQR, 135-154 mg) in group B1. Furthermore, the awakening concentration was 1.1 µg/mL (IQR, 0.9-1.2 µg/mL) in group B2 and 1.2 µg/mL (IQR, 1.025-1.5 µg/mL) in group B1. Notably, the propofol TCI plus butorphanol groups (groups B1 and B2) had a lower incidence of anesthesia AEs, when compared to group C. Furthermore, no significant differences were observed in the rates of AEs in perianesthesia, including hypoxemia, sinus bradycardia, hypotension, nausea and vomiting, and vertigo, among group C, group B1 and group B2. CONCLUSION: The combined use with butorphanol reduces the EC50 of propofol TCI for anesthesia. The decrease in propofol might contribute to the reduced anesthesia-related AEs in patients undergoing sedated colonoscopy.

Analysis of survival factors after hepatic resection for colorectal cancer liver metastases: Does the R1 margin matter?

Introduction: The effect of liver margin on colorectal cancer liver metastases (CRLM) after hepatectomy has been controversial. In this study, we conducted a postoperative follow-up study of 205 patients with CRLM to clarify whether a positive margin is significant and to define the risk factors affecting CRLM survival. Methods: The data of 205 patients with CRLM who underwent surgical treatment at the Third Hospital of Peking University in the Department of General Surgery from January 2009 to December 2020 were retrospectively analyzed. The general data, surgical data and postoperative follow-up of the patients were statistically analyzed. Results: There were 130 cases (63.4%) of R0 resection and 75 cases (36.6%) of R1 resection. There were 136 males and 69 females, age 61 ± 11 years, and body mass index (BMI 24.5 ± 3.3 kg/m2). The overall survival rates at 1, 3, and 5 years for the entire cohort were 93.4%, 68.4%, and 45.5% in the R0 resection group vs. 93.2%, 53.7%, and 42% in the R1 resection group, respectively, which were not statistically significant (P = 0.520). The 1-, 3-, and 5-year disease-free survival rates of 63.2%, 33.3%, and 29.7% were significantly better in the R0 resection group than in the R1 resection group of 47.9%, 22.7%, and 17.7% (P = 0.016), respectively. After multivariable analysis, carbohydrate antigen 19-9 (CA19-9) > 39 U/ml (HR = 2.29, 95% CI: 1.39-3.79, P = 0.001), primary tumor perineural invasion (HR = 1.78, 95% CI: 1.01-3.13, P = 0.047), and BMI > 24 kg/m2 (HR = 1.75, 95% CI: 1.05-2.93, P = 0.033) were independently associated with poorer overall patient survival. The number of liver metastases >2 (HR = 1.65, 95% CI: 1.10-2.47, P = 0.016), the maximum diameter of metastases ≥50 mm (HR = 1.67, 95% CI: 1.06-2.64, P = 0.026), and vascular invasion of the primary tumor (HR = 1.65, 95% CI: 1.03-2.64, P = 0.038) were also independently associated with poorer disease-free survival. Conclusion: In patients undergoing hepatectomy for CRLM, the negative effect of the R1 margin should be downplayed, and although the disease-free survival of the R1 margin is shorter than that of the R0 margin, it has no impact on overall survival. To improve overall survival, extra attention should be given to the factors of preoperative BMI, preoperative CA19-9, and the presence of perineural invasion of the primary tumor.

Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer.

Morphine is an opioid analgesic drug commonly used for pain relief in cancer patients. Here, we report that morphine enhances the mammosphere forming capacity and increases the expression of stemness-related transcription factors Oct4, Sox2 and Nanog. Treatment with morphine leads to enrichment of a side population fraction in MCF-7 cells and the CD44+/CD24(-/low) population in BT549 cells. Consistently, morphine activates Wnt/ß-catenin signaling to induce epithelial to mesenchymal transition and promotes metastasis. Moreover, morphine decreases the sensitivity of traditional anti-cancer drugs in breast cancer cells. Nalmefene, an antagonist of morphine, reverses morphine-induced cancer stem cell properties and chemoresistance in breast cancer. In addition, nalmefene abolishes morphine enhancing tumorigenesis in a NOD/SCID mouse model. In conclusion, our findings demonstrate that morphine contributes to chemoresistance via expanding the population of cancer stem cells and promotes tumor growth, thereby revealing a novel role of morphine and providing some new guides in clinical use of morphine.