Continuous Oral Administration of the Superantigen Staphylococcal Enterotoxin C2 Activates Intestinal Immunity and Modulates the Gut Microbiota in Mice.

Staphylococcal Enterotoxin C2 (SEC2), a classical superantigen, is an antitumor immunotherapy agent. However, the injectable formulation of SEC2 limits its clinical application. Here, it is reported that oral administration of SEC2 activates the intestinal immune system and benefits intestinal health in a mouse model. These results indicate that intact SEC2 is detected in the stomach, intestine, and serum after oral administration. Continuous oral administration of SEC2 activates immune cells in gut-associated lymphoid tissues, promoting extensive differentiation and proliferation of CD4+ and CD8+ T cells and CD19+ B cells, leading to increased production of cytokines and secretory immunoglobulin A. SEC2 also enhances intestinal barrier function, as demonstrated by an increased villus length/crypt depth ratio and elevated expression of mucins and tight junction proteins. Additionally, SEC2 indirectly influenced gut microbiota, reinforcing potential probiotics and short-chain fatty acid synthesis. Enhanced differentiation of T and B cells in the spleen, coupled with elevated serum interleukin-2 levels, suggests systemic immune enhancement following oral administration of SEC2. These findings provide a scientific basis for the development of SEC2 as an oral immunostimulant for immune enhancement and anti-tumor immunotherapy.

A reliable and quick method for screening alternative splicing variants for low-abundance genes.

Alternative splicing (AS) is a universal phenomenon in eukaryotes, and it is still challenging to identify AS events. Several methods have been developed to identify AS events, such as expressed sequence tags (EST), microarrays and RNA-seq. However, EST has limitations in identifying low-abundance genes, while microarray and RNA-seq are high-throughput technologies, and PCR-based technology is needed for validation. To overcome the limitations of EST and shortcomings of high-throughput technologies, we established a method to identify AS events, especially for low-abundance genes, by reverse transcription (RT) PCR with gene-specific primers (GSPs) followed by nested PCR. This process includes two major steps: 1) the use of GSPs to amplify as long as the specific gene segment and 2) multiple rounds of nested PCR to screen the AS and confirm the unknown splicing variants. With this method, we successfully identified three new splicing variants, namely, GenBank Accession No. HM623886 for the bdnf gene (GenBank GeneID: 12064), GenBank Accession No. JF417977 for the trkc gene (GenBank GeneID: 18213) and GenBank Accession No. HM623888 for the glb-18 gene (GenBank GeneID: 172485). In addition to its reliability and simplicity, the method is also cost-effective and labor-intensive. In conclusion, we developed an RT-nested PCR method using gene-specific primers to efficiently identify known and novel AS variants. This approach overcomes the limitations of existing methods for detecting rare transcripts. By enabling the discovery of new isoforms, especially for low-abundance genes, this technique can aid research into aberrant splicing in disease. Future studies can apply this method to uncover AS variants involved in cancer, neurodegeneration, and other splicing-related disorders.

Long-term relapse-free survival enabled by integrating targeted antibacteria in antitumor treatment.

The role of tumor-resident intracellular microbiota (TRIM) in carcinogenesis has sparked enormous interest. Nevertheless, the impact of TRIM-targeted antibacteria on tumor inhibition and immune regulation in the tumor microenvironment (TME) remains unexplored. Herein, we report long-term relapse-free survival by coordinating antibacteria with antitumor treatment, addressing the aggravated immunosuppression and tumor overgrowth induced by TRIM using breast and prostate cancer models. Combining Ag+ release with a Fenton-like reaction and photothermal conversion, simultaneous bacteria killing and multimodal antitumor therapy are enabled by a single agent. Free of immune-stimulating drugs, the agent restores antitumor immune surveillance and activates immunological responses. Secondary inoculation and distal tumor analysis confirm lasting immunological memory and systemic immune responses. A relapse-free survival of >700 days is achieved. This work unravels the crucial role of TRIM-targeted antibacteria in tumor inhibition and unlocks an unconventional route for immune regulation in TME and a complete cure for cancer.

Clinical Efficacy of Neuroendoscopy Combined with Intracranial Pressure Monitoring for the Treatment of Hypertensive Intracerebral Hemorrhage.

OBJECTIVE: To compare the differences in postoperative complications and prognosis between patients treated with neuroendoscopy versus conventional craniotomy surgery for hypertensive intracerebral hemorrhage (HICH). METHODS: In this retrospective study, a total of 107 patients with HICH were included. Among them, 58 underwent neuroendoscopy (Group A), while 49 underwent conventional craniotomy under microscopic guidance (Group B). Intracranial pressure monitoring was applied in both groups. The clinical data, incidence of postoperative complications, preoperative and postoperative intracranial pressure values, and rate of favorable prognosis were compared between the 2 groups. RESULTS: No significant difference in baseline clinical data upon admission was observed between the 2 groups (P > 0.05). The preoperative intracranial pressure did not differ between the 2 groups (P > 0.05), but the postoperative intracranial pressure in Group A was significantly lower than that in Group B (P < 0.05). After intervention with the different surgical approaches, Group A showed a significantly lower incidence of postoperative cerebral infarction and a significantly higher rate of favorable prognosis compared with Group B (P < 0.05). CONCLUSIONS: Neuroendoscopy combined with Intracranial pressure monitoring is a safe and reliable approach for the treatment of HICH that reduces the incidence of postoperative cerebral infarction and improves the recovery of neurological function after surgery.

Laparoscopic versus open gastrectomy for locally advanced gastric cancer after neoadjuvant chemotherapy: a comprehensive contrastive analysis with propensity score matching.

BACKGROUND: Laparoscopic gastrectomy (LG) is increasingly applied in locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy (NC). However, there is no study to comprehensively evaluate the clinicopathological, prognostic, and laboratory data such as nutrition, immune, inflammation-associated indexes, and tumor markers between LG and open gastrectomy (OG) for LAGC following NC. METHODS: The clinicopathological, prognostic, and laboratory data of LAGC patients with clinical stage of cT2-4aN1-3M0 who underwent gastrectomy after NC were retrospectively collected. The effects of LG and OG were compared after propensity score matching (PSM). RESULTS: This study enrolled 148 cases, of which 110 cases were included after PSM. The LG group had a shorter length of incision (P < 0.001) and was superior to OG group in terms of blood loss (P < 0.001), postoperative first flatus time (P < 0.001), and postoperative first liquid diet time (P = 0.004). No significant difference was found in postoperative complications (P = 0.482). Laboratory results showed that LG group had less reduced red blood cells (P = 0.039), hemoglobin (P = 0.018), prealbumin (P = 0.010) in 3 days after surgery, and less reduced albumin in 1 day (P = 0.029), 3 days (P = 0.015), and 7 days (P = 0.035) after surgery than the OG group. The systemic immune-inflammation index and systemic inflammatory response index were not significantly different between the two groups. As for oncological outcomes, there were no significant differences in postoperative tumor markers of CEA (P = 0.791), CA199 (P = 0.499), and CA724 (P = 0.378). The 5-year relapse-free survival rates (P = 0.446) were 46.9% and 43.3% in the LG and OG groups, with the 5-year overall survival rates (P = 0.742) being 46.7% and 52.1%, respectively; the differences were not statistically significant. Multivariate Cox regression analysis revealed that tumor size ≥ 4 cm (P = 0.021) and the absence of postoperative adjuvant chemotherapy (P = 0.012) were independent risk factors for overall survival. CONCLUSIONS: LG has faster gastrointestinal recovery, better postoperative nutritional status, and comparable oncological outcomes than OG, which can serve as an alternative surgical method for LAGC patients after NC.

Staphylococcal Enterotoxin C2 Mutant-Induced Antitumor Immune Response Is Controlled by CDC42/MLC2-Mediated Tumor Cell Stiffness.

As a biological macromolecule, the superantigen staphylococcal enterotoxin C2 (SEC2) is one of the most potent known T-cell activators, and it induces massive cytotoxic granule production. With this property, SEC2 and its mutants are widely regarded as immunomodulating agents for cancer therapy. In a previous study, we constructed an MHC-II-independent mutant of SEC2, named ST-4, which exhibits enhanced immunocyte stimulation and antitumor activity. However, tumor cells have different degrees of sensitivity to SEC2/ST-4. The mechanisms of immune resistance to SEs in cancer cells have not been investigated. Herein, we show that ST-4 could activate more powerful human lymphocyte granule-based cytotoxicity than SEC2. The results of RNA-seq and atomic force microscopy (AFM) analysis showed that, compared with SKOV3 cells, the softer ES-2 cells could escape from SEC2/ST-4-induced cytotoxic T-cell-mediated apoptosis by regulating cell softness through the CDC42/MLC2 pathway. Conversely, after enhancing the stiffness of cancer cells by a nonmuscle myosin-II-specific inhibitor, SEC2/ST-4 exhibited a significant antitumor effect against ES-2 cells by promoting perforin-dependent apoptosis and the S-phase arrest. Taken together, these data suggest that cell stiffness could be a key factor of resistance to SEs in ovarian cancer, and our findings may provide new insight for SE-based tumor immunotherapy.

Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort.

Objectives: Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. Methods: The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. Results: A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4 min vs. 237.6 ± 68.4 min, P=0.732), intraoperative blood loss (157.8 ± 75.9 ml vs. 149.1 ± 92.5 ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Conclusion: Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.

Biological effects of exposure to 2650 MHz electromagnetic radiation on the behavior, learning, and memory of mice.

BACKGROUND: With the development of communication technology, the public is paying increasing attention to whether electromagnetic radiation is harmful to health. Mobile phone communication has entered the 5G era, and there are almost no reports on electromagnetic radiation at 2650 MHz. Therefore, it is necessary to evaluate the risk of adverse effects of 5G mobile phone EMR exposure on the human brain. METHODS: Male animals were continuously exposed to 2650 MHz-EMR for 28 days with a whole-body averaged specific absorption rate (WBSAR) of 2.06 W/kg for 4 h per day. Mouse behavior was assessed using the open-field test (OFT), elevated-plus maze (EPM), and tail suspension test (TST). The Morris water maze (MWM), HE staining, and TUNEL staining were used to evaluate the spatial memory ability and pathological morphology of hippocampal dentate gyrus cells. Additionally, the expression levels of brain-derived neurotrophic factor (BDNF), aminobutyric acid (GABA), and glucocorticoid (GR) in the hippocampus were detected by western blotting and immunohistochemistry, while the corticosterone (CORT) level in serum was detected by ELISA. RESULTS: In the OFT, the total distance traveled, central distance traveled, and residence time significantly decreased in the EMR exposure group (p < .05). In EPM, the percentage of the number of times to open the arm and the percentage of time to open the arm significantly decreased in the EMR exposure group. However, in the TST, the two groups had no significant difference in the 4-min immobility time. In the MWM, the escape latency of the EMR exposure group was shorter than that of the control group, with no significant difference. Furthermore, CORT levels in serum were significantly increased in the EMR exposure group (p < .05), while the expression of BDNF and GR proteins in the hippocampus was reduced (p < .05), but there was no significant difference in GABA expression. CONCLUSIONS: Our results indicate that exposure to 2650 MHz-EMR (WBSAR: 2.06 W/kg, 28 days, 4 h per day) had no significant effect on the spatial memory ability of mice (in comparison to little effect). The exposure may be associated with anxiety-like behavior in mice but not related to depression-like behavior in mice.

Exosome-Delivered circSTAU2 Inhibits the Progression of Gastric Cancer by Targeting the miR-589/CAPZA1 Axis.

Background: Circular RNAs (circRNAs) are endogenous noncoding RNAs that play vital roles in many biological processes, particularly in human cancer. Recent studies indicate that circRNAs play an important role in tumor progression through exosomes. However, the specific functions of gastric cancer-derived exosomes and the role of circSTAU2 in gastric cancer (GC) remain largely unknown. Methods: Differentially expressed circRNAs in GC were identified by circRNA microarrays analysis and quantitative real-time polymerase chain reaction (qRT-PCR). The role of circSTAU2 in GC was verified by circSTAU2 knockdown and overexpression with functional assays both in vitro and in vivo. Fluorescence in situ hybridization (FISH), immunofluorescence, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, qRT-PCR and Western blot were adopted to evaluate the expression and regulatory mechanism of MBNL1, circSTAU2, miR-589 and CAPZA1. Furthermore, the role of exosomes was demonstrated by transmission electron microscopy and nano-sight particle tracking analysis. Results: CircSTAU2, mainly localized in the cytoplasm, was significantly downregulated in GC. CircSTAU2 overexpression inhibited GC cell proliferation, invasion and migration both in vitro and in vivo, while circSTAU2 knockdown had the inverse effect. CircSTAU2 could be wrapped in exosomes and delivered to recipient cells, and functioned as a sponge for miR-589 to relieve its inhibitory effect on CAPZA1, thus inhibiting GC progression. Furthermore, MBNL1 acted as the upstream RNA-binding protein of circSTAU2 and significantly influenced the circularization and expression of circSTAU2. Conclusion: Exosome-delivered circSTAU2 may act as a tumor suppressor that restrains GC progression via miR-589/CAPZA1 axis, which demonstrates a potential therapeutic target for GC.

Centrosomal protein 120 promotes centrosome amplification and gastric cancer progression via USP54-mediated deubiquitination of PLK4.

Centrosomal protein 120 (CEP120) is a 120 kDa centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome duplicate abnormality, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.

Two pairs of epimers and three undescribed diterpenoids from Pseudocaryopteris paniculata.

A phytochemical investigation on the petroleum ether partition of the whole plant of Pseudocaryopteris paniculata, yield seven new compounds: one phytanes diterpenoid (2Z,6E,10E) 14-keto-2,6,10-trimethyl pentadeca-2,6,10-trien-1-carboxylic acid (1), five clerodane diterpenoids: paniculatins A-E (2, 3a/3b, 4a/4b), one abietane diterpenoid: ent-uncinatone (5), together with 12 known compounds. Their structures were elucidated on the basis of 1D and 2D Nuclear Magnetic Resonance （NMR_, Infrared Radiation (IR), and mass spectroscopic data. Compound 2, 5, and 11 showed weak selective cytotoxic activity of 11 human cancer cell lines.

Lymph node ratio is a prospective prognostic indicator for locally advanced gastric cancer patients after neoadjuvant chemotherapy.

BACKGROUND: The accuracy of lymph node ratio (LNR) as a prognostic index remains to be proven for gastric cancer patients after neoadjuvant chemotherapy (NACT). This study sought to investigate the prognostic value of LNR in locally advanced gastric cancer (LAGC) patients after NACT. METHODS: LAGC patients with clinical TNM stages 2-3, Her2(-), and Eastern Cooperative Oncology Group, scores 0-2 are routinely scheduled with NACT. Patients with LAGC after NACT and surgical operation between January 2012 and October 2020 were retrospectively reviewed. The correlation between LNR and survival was investigated. RESULTS: Overall, 148 patients were enrolled: 103 with low-LNR (LNR ≤ 30%) and 45 with high-LNR (LNR > 30%). Approximately, 50.5% and 24.4% patients responded to NACT at the primary site in the low-LNR and high-LNR groups, respectively. The overall survival (OS) and progression-free survival (PFS) of low-LNR group were considerably better than those of high-LNR group (3-year OS: 81.9% vs 18.5%, P < 0.001; 3-year PFS: 72.6% vs 13.5%, P < 0.001). In the low-LNR group, OS and PFS were superior in patients with tumor regression grade (TRG) 0-2 than in those with TRG 3 (3-year OS: 89.2% vs 73.2%, P = 0.086; 3-year PFS: 80.3% vs 66.5%, P = 0.036). In association with OS and PFS, the degree of tumor differentiation, TRG, and LNR were identified as predictive factors, and LNR was identified as the independent prognostic factor in univariate and multivariate analyses, respectively. CONCLUSIONS: LNR is a prospective index of prognosis in patients with LAGC after NACT.

Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation.

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.

Induction of CD4+ regulatory T cells by stimulation with Staphylococcal Enterotoxin C2 through different signaling pathways.

As a member of superantigens, Staphylococcal Enterotoxin C2 (SEC2) can potently activate T cells expressing specific Vß repertoires and has been applied in clinic for tumor immunotherapy in China for more than 20 years. However, excessive activation of T cells by over-stimulation with superantigen are always followed by eliciting regulatory T cells (Tregs) induction and functional immunosuppression, which brings uncertainties to SEC2 application in tumor immunotherapy. In this study, we found that SEC2 could induce CD4+CD25+Foxp3+ Tregs from the murine splenocytes in dose and time related manners. The induced Tregs with high expression of GITR and CTLA-4 and low expression of CD127 were TCR Vß8.2-specific and have character of IL-10 production in a SEC2 dose-depended manner. Importantly, SEC2-induced CD4+ Tregs showed the potent capacity of suppressing proliferation of intact murine splenocytes response to SEC2. Furthermore, by using specific inhibitors or neutralizing antibody, we proved that the signaling pathways of TCR-NFAT/AP-1, IL-2-STAT5, and TGF-ß-Smad3 play crucial roles in Tregs induction by SEC2. These findings will help us better understand the balance of immune stimulation and immunosuppression mediated by SEC2 and provide valuable guidance for SEC2 application in antitumor immunology.

Effect of operative trauma and multiple propofol anesthesia on neurodevelopment and cognitive function in developmental rats.

To investigate the effect of multiple propofol anesthesia and operative trauma on neuroinflammation and cognitive function in development rats and its mechanism. A total of 104 13-day-old neonatal Sprague-Dawley rats were randomly divided into 4 groups with 26 rats in each group: control group was treated with saline q.d for propofol group was treated with propofol q.d for surgery group received abdominal surgery under local anesthesia and then treated with saline q.d for surgery with propofol group received propofol anesthesia plus abdominal surgery under local anesthesia with ropivacaine at d1, then treated with propofol q.d for At d2 of experiment, 13 rats from each group were sacrificed and brain tissue samples were taken, the concentration of TNF-α in hippocampus was detected with ELISA, the expression of caspase-3 and c-fos in hippocampal tissue was determined with immunohistochemical method, the number of apoptotic neurons in hippocampus was examined with TUNEL assay. Morris water maze test was used to examine the cognitive function of the rest rats at the age of 60 d, and the TNF-α concentration, caspase-3, c-fos expressions and the number of apoptotic neurons in hippocampus were also detected. Compared with control group, TNF-α concentration, caspase-3, c-fos expression and the neuroapoptosis in hippocampus increased significantly in other three groups (all <0.05). Compared with surgery group, propofol group and surgery with propofol group showed increased TNF-α level, caspase-3 and c-fos expressions and apoptotic cell numbers (all <0.05), but there was no significant difference between last two groups (all >0.05). Morris water maze test showed that there were no significant differences in swimming speed, escape latency, target quadrant residence time and crossing times among groups (all >0.05). TNF-α level, expressions of caspase-3 and c-fos and apoptotic cell numbers in hippocampus had no significant differences among the 4 adult rats groups (all >0.05). Abdominal surgery and multiple propofol treatment can induce neuroinflammation and neuroapoptosis in hippocampus of neonatal rats, however, which may not cause adverse effects on neurodevelopment and cognitive function when they grown up.

Intraoperative Vitamin C Reduces the Dosage of Propofol in Patients Undergoing Total Knee Replacement.

PURPOSE: Propofol is commonly used as an intravenous anesthetic in surgical patients. However, its usage is associated with adverse effects. Auxiliary medication can reduce the dose of intravenous anesthetics. Hence, we investigated whether vitamin C could lower propofol dosage in elderly patients undergoing total knee replacement surgery. PATIENTS AND METHODS: The trial was carried out in PLA General Hospital in Beijing, China. We enrolled patients aged ≥50 years who were undergoing unilateral total knee arthroplasty with total intravenous anesthesia combined with lumbar sciatic nerve block. The patients were randomly assigned to either the vitamin C (Vc) group (0.067 g/kg) or the control group (an equivalent dose of normal saline). Nerve block was done for all the patients before the general anesthesia. The same depth of anesthesia was maintained during the operation. We compared the propofol dosage and adverse events (eg hypotension) during anesthesia between the two groups. This study was registered with the Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-16010112. RESULTS: There were significant differences in the total infusion dose (Vc group: 704.3 ± 188.6 mg; control group: 888.6 ± 232.7 mg; p = 0.016) and the average maintenance dose of propofol (Vc group: 5.8 ± 1.0 mg/kg/h; control group: 6.9 ± 1.6 mg/kg/h; p = 0.013). But there were no significant differences in the induction dose of propofol (control group: 90 mg, range 80-115 mg; Vc group: 100 mg, range 90-110 mg, p = 0.379) between the Vc and control groups. Furthermore, there were no significant differences in the hemodynamics and the incidence of intraoperative hypotension. CONCLUSION: Vitamin C can reduce the dosage of propofol in patients undergoing total knee replacement.

Comorbidity, lifestyle factors, and sexual satisfaction among Chinese cancer survivors.

OBJECTIVES: This study aims to explore the prevalence of sexual satisfaction among Chinese cancer survivors, and explore the association of sexual satisfaction with comorbidity and lifestyle factors. METHODS: A cross-sectional study was performed among 3996 Chinese cancer survivors recruited at Shanghai Cancer Rehabilitation Club from March to April 2017. Data were collected through self-reported questionnaires. The questionnaire includes information about demographic, cancer characteristics, comorbidities, lifestyle factors, and sexual satisfaction. Sexual satisfaction was measured by a single-item scale. The distribution of sexual satisfaction among different demographic and cancer characteristics was compared using the chi-squared test. Logistic regression models were conducted to assess the effects of lifestyle factors, comorbidities on sexual satisfaction after adjustment for demographic and cancer characteristics. RESULTS: More than 40% of male and female cancer survivors reported no sexual satisfaction. Sexual satisfaction of cancer survivors is significantly associated with both the number and the type of comorbidities. Heart disease, musculoskeletal system disease, diabetes, and hyperlipidemia are the comorbidities significantly associated with sexual satisfaction of cancer survivors. Lifestyle factors other than smoking, including exercise or fitness, drinking alcohol, and eating fruits and vegetables are significantly correlated with sexual satisfaction. Besides, all of the above associations show gender differences. In addition, demographic characteristics include sex, age, marital status, living status, and average monthly income are also significantly associated with sexual satisfaction of cancer survivors. CONCLUSION: Comorbidity and lifestyle factors are associated with sexual satisfaction of cancer survivors, and the associations show gender differences. Improving the lifestyles of cancer survivors, and controlling and reducing their comorbidities are important for improving their sexual satisfaction.

Staphylococcal Enterotoxin C2 Mutant-Directed Fatty Acid and Mitochondrial Energy Metabolic Programs Regulate CD8+ T Cell Activation.

CD8+ T cells can switch between fatty acid catabolism and mitochondrial energy metabolism to sustain expansion and their cytotoxic functions. ST-4 is a TCR-enhanced mutant derived from superantigen staphylococcal enterotoxin C2 (SEC2), which can hyperactivate CD4+ T cells without MHC class II molecules. However, whether ST-4/SEC2 can enhance metabolic reprogramming in CD8+ T cells remains poorly understood. In this study, we found that ST-4, but not SEC2, could induce proliferation of purified CD8+ T cell from BALB/c mice in Vß8.2- and -8.3-specific manners. Results of gas chromatography-mass spectroscopy analysis showed that fatty acid contents in CD8+ T cells were increased after ST-4 stimulation. Flow cytometry and Seahorse analyses showed that ST-4 significantly promoted mitochondrial energy metabolism in CD8+ T cells. We also observed significantly upregulated levels of gene transcripts for fatty acid uptake and synthesis, and significantly increased protein expression levels of fatty acid and mitochondrial metabolic markers of mTOR/PPARγ/SREBP1 and p38-MAPK signaling pathways in ST-4-activated CD8+ T cells. However, blocking mTOR, PPARγ, SREBP1, or p38-MAPK signals with specific inhibitors could significantly relieve the enhanced fatty acid catabolism and mitochondrial capacity induced by ST-4. In addition, blocking these signals inhibited ST-4-stimulated CD8+ T cell proliferation and effector functions. Taken together, our findings demonstrate that ST-4 enhanced fatty acid and mitochondria metabolic reprogramming through mTOR/PPARγ/SREBP and p38-MAPK signaling pathways, which may be important regulatory mechanisms of CD8+ T cell activation. Understanding the effects of ST-4-induced regulatory metabolic networks on CD8+ T cells provide important mechanistic insights to superantigen-based tumor therapy.

Cytotoxic Diterpenoids from Caryopteris aureoglandulosa.

Seven new (1-7) and 11 known diterpenoids were isolated and identified from Caryopteris aureoglandulosa. These diterpenoids were structurally determined by HRESIMS and NMR spectroscopic analyses, single-crystal X-ray diffraction, and ECD data. Structurally, aureoglandulosin A (1) is a highly oxygenated abietane diterpenoid with an unprecedented 7/6/6/5-ring system. Aureoglandulosins B (2) and C (3) represent naturally occurring new diterpenoids with an unusual 6/6/6/5-ring system. Additionally, the configurations of two known abietane diterpenoids 11 and 12 were determined by X-ray crystallographic data analysis for the first time. A plausible biosynthetic pathway for compounds 1-3 is proposed. The cytotoxicity of all isolates was evaluated, and compounds 1 and 11 exhibited significant cytotoxic activity against some cell lines with IC50 values in the range 1.6-8.2 µM.

An iRGD peptide fused superantigen mutant induced tumor-targeting and T lymphocyte infiltrating in cancer immunotherapy.

Solid tumors are intrinsically resistant to immunotherapy because of the major challenges including the immunosuppression and poor penetration of drugs and lymphocytes into solid tumors due to the complicated tumor microenvironment (TME). Our previous study has created a novel superantigen mutant ST-4 to efficiently active the T lymphocytes and alleviate immune suppression. In the present study, to accumulate ST-4 into the TME, we constructed a recombinant protein, ST-4-iRGD, by fusing ST-4 to a tumor-homing peptide, iRGD. We hypothesized that ST-4-iRGD could internalize into the TME through iRGD-mediated tumor targeting and tumor tissue penetrating to activate the regional immunoreaction. The results of in vitro studies showed that ST-4-iRGD achieved improved tumor targeting and cytotoxicity in mouse B16F10 melanoma cells. The iRGD-mediated tumor tissue penetration was further confirmed by imaging and immunofluorescence studies in vivo, wherein higher distribution of ST-4-iRGD was observed in the mouse 4T1 breast tumor model. Moreover, ST-4-iRGD exhibited enhanced anti-solid tumor characteristics and induced improved lymphocyte infiltration in the B16F10 and 4T1 models. In conclusion, using iRGD to facilitate better dissemination of the therapeutic agent ST-4 throughout a solid tumor mass is feasible, and ST-4-iRGD may be a potential candidate for efficient cancer immunotherapy in the future.