Combined sevoflurane-dexmedetomidine and nerve blockade on post-surgical serum oxidative stress biomarker levels in thyroid cancer patients.

BACKGROUND: The incidence of thyroid cancer is increasing annually. Clinical routine thyroid surgery can be performed under a cervical plexus block, but cannot mediate the stress response during the surgery. If thyroid surgery is performed under nerve block, an inappropriate level of blockade may occur. Similarly, the stress response caused by surgery is more serious than that caused by conventional anesthesia. Therefore, it is important to combine blockade with more effective anesthesia methods. AIM: To investigate the effects of combining sevoflurane-dexmedetomidine inhalation general anesthesia with the cervical plexus nerve block on the post-surgical levels of the serum oxidative stress biomarkers levels in thyroid cancer patients. METHODS: We enrolled 96 thyroid cancer patients admitted to the hospital between January 2019 and December 2020. Participants were divided into a control group (n = 47) and an experimental group (n = 49). The experimental group received a combination of inhaled sevoflurane-dexmedetomidine and cervical plexus block, while the control group received conventional general anesthesia. The groups were compared for serum levels of monocyte chemotactic protein-1 (MCP-1) and glutathione peroxidase (GSH-Px) before and after surgery, and the adrenocorticotropic hormone (ACTH) and norepinephrine (NE) levels at 1 and 12 h post-surgery. The Bispectral index (BIS) and the incidence of anesthesia side effects were also compared. RESULTS: Following surgery, MCP-1 was significantly lower in the experimental group compared to the control group, whereas GSH-Px was significantly higher than that in the control group (P < 0.001). The serum ACTH and NE levels were significantly lower in the experimental group than those the control group at 1 and 12 h post-surgery (P < 0.001). BIS was significantly lower in the experimental group than that in the control group at 20 minutes into the operation, but the direction of the difference was reversed at eye opening (P < 0.001). The incidence of side effects was 10.20% (5/49) and 12.76% (6/47) in the experimental and control groups, respectively, the difference being non-significant. CONCLUSION: Sevoflurane-dexmedetomidine inhalation general anesthesia combined with cervical plexus nerve block can reduce the postoperative stress and inflammatory responses in thyroid cancer patients, while maintaining high anesthesia effectiveness and safety.

Characterization of CD103+ CD8+ tissue-resident T cells in esophageal squamous cell carcinoma: may be tumor reactive and resurrected by anti-PD-1 blockade.

Though therapy that promotes anti-tumor response about CD8+ tumor-infiltrating lymphocytes (TILs) has shown great potential, clinical responses to CD8+ TILs immunotherapy vary considerably, largely because of different subpopulation of CD8+ TILs exhibiting different biological characters. To define the relationship between subpopulation of CD8+ TILs and the outcome of antitumor reaction, the phenotype and function of CD103+ CD8+ TILs in esophageal squamous cell carcinoma (ESCC) were investigated. CD103+ CD8+ TILs were presented in ESCC, which displayed phenotype of tissue-resident memory T cells and exhibited high expression of immune checkpoints (PD-1, TIM-3). CD103+ CD8+ TILs were positively associated with the overall survivals of ESCC patients. This population of cells elicited potent proliferation and cytotoxic cytokine secretion potential. In addition, CD103+ CD8+ TILs were elicited potent anti-tumor immunity after anti-PD-1 blockade and were not affected by chemotherapy. This study emphasized the feature of CD103+ CD8+ TILs in immune response and identified potentially new targets in ESCC patients.

Intrinsic Expression of Immune Checkpoint Molecule TIGIT Could Help Tumor Growth in vivo by Suppressing the Function of NK and CD8+ T Cells.

TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro, the tumor growth in mice was considerably inhibited. TIGIT knockout led to the increase of IFN-γ secretion by NK and CD8+ T cells. Further, in BABL/c nude mice, CD8+ T cells depleting mice and NK cells depleting nude mice, the promotion of tumor growth was significantly diminished, suggesting that both NK cells and CD8+ T cells were involved in the tumor promoting process mediated by intrinsic TIGIT. In addition, blocking TIGIT/PVR interaction by the antibody or recombinant PVR protein could elicit anti-tumor effects by facilitating the tumor infiltration and restoring the function of CD8+ T cells, and the antibody-mediate TIGIT blockade could inhibit MC38 tumor growth through blocking TIGIT expressed on tumor cells. We therefore propose a novel TIGIT/PVR interaction mode that tumor intrinsic TIGIT delivers inhibitory signals to CD8+ T cells and NK cells by engaging with PVR.

miR-1306-3p targets FBXL5 to promote metastasis of hepatocellular carcinoma through suppressing snail degradation.

This study aimed to elucidate the effect of miR-1306-3p on metastasis of hepatocellular carcinoma (HCC) and potential mechanism involved. miR-1306-3p promoted migration and invasion of HCC in vivo and in vitro. Moreover, miR-1306-3p inhibited snail to enhance its expression via directly targeting FBXL5, thus inducing the epithelial-mesenchymal transition (EMT) in HCC. Intriguingly, miR-1306-3p expression was transcriptionally enhanced by FoxM1. Consistently, miR-1306-3p was upregulated in HCC compared with paracarcinoma and correlated with poor prognosis of HCC patients. Our researches suggest that miR-1306-3p is a tumor enhancer in regulating of HCC metastasis, and miR-1306-3p may be clinically utilized as a factor for the clinical diagnosis and prognosis of HCC.

Use of epoprostenol to treat severe pulmonary vasoconstriction induced by protamine in cardiac surgery.

Since there were a few articles to report the treatment of severe pulmonary vasoconstriction induced by protamine in cardiac surgery, we described the use of epoprostenol to reverse this condition.A total of 5 cases of severe pulmonary vasoconstriction induced by protamine in cardiac surgery were reviewed. The demographic, clinical data and treatment process were obtained. All the patients were followed up.Severe pulmonary vasoconstriction was occurred 4 to 10 minutes after protamine infusion. The primary sign was sudden hypotension, the pulmonary artery pressure was increased gradually, the arterial oxygen partial pressure was decreased in all the patients. Epoprostenol was infused via pulmonary artery catheter at dosage of 20 to 40 ng/kg·min in all the patients, 2 patients were underwent re-cardiac pulmonary bypass assistance. The hemodynamic instability status lasted 40 to 65 minutes respectively. All the patients were recovered uneventfully.All physicians should alert to the incidence of severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Use epoprostenol through pulmonary artery catheter could treat pulmonary artery vasoconstriction effectively and safely.

Positive Correlation Between Regional Cerebral Oxygen Saturation and Mixed Venous Oxygen Saturation During Off-Pump Coronary Artery Bypass Surgery.

BACKGROUND: The balance of oxygen delivery and consumption is essential in patients who are critically ill. Mixed venous oxygen saturation (Sv̄O2 ) is a standard method to evaluate oxygen delivery and consumption during anesthesia. However, Sv̄O2 is monitored through a pulmonary artery catheter, which is invasive. Regional cerebral oxygenation (rScO2) reflects oxygen saturation in a small region of the frontal lobes and is monitored noninvasively through near-infrared spectroscopy. In the present study, the correlation between rScO2 and Sv̄O2 was calculated during off-pump coronary artery bypass grafting surgery to determine whether a positive correlation exists between rScO2 and Sv̄O2 . METHODS: A total of 56 subjects were consecutively enrolled in the study. Then rScO2 and Sv̄O2 were simultaneously monitored. The parameters were recorded at 5 time points: T1, 10 min after intubation (1.0 FIO2 for 10 min); T2, 20 min after intubation (0.60 FIO2 for 10 min); T3, at the end of the revascularization of the left anterior descending artery (0.60 FIO2 ); T4, after protamine infusion (0.60 FIO2 ); and T5, 10 min after protamine infusion (1.0 FIO2 for 10 min). The correlation between rScO2 and Sv̄O2 and the variation trend between rScO2 and Sv̄O2 when FIO2 increased from 0.60 to 1.0 were analyzed. RESULTS: There was a significant positive correlation between rScO2 and Sv̄O2 at these 5 time points (r 2 = 0.77, 0.81, 0.70, 0.83, and 0.92, respectively). There also was a significant positive correlation between Δ rScO2 and Δ Sv̄O2 (n = 112, r 2 = 0.72, P < .001). Linear regression analysis revealed that Sv̄O2 had a positive correlation with rScO2 and cardiac output (r 2 = 0.68, P = .013). CONCLUSIONS: There was a positive correlation between rScO2 and Sv̄O2 during off-pump coronary artery bypass grafting surgery, and there also was a positive correlation in the variation trend between rScO2 and Sv̄O2 .

LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression.

Liver cancer has a tendency to develop asymptomatically in patients, so most patients are diagnosed at a later stage. Accumulating evidence implicates that liver tumour-initiating cells (TICs) as being responsible for liver cancer initiation and recurrence. However, the molecular mechanism of liver TIC self-renewal is poorly understood. Here we discover that a long noncoding RNA (lncRNA) termed LncSox4 is highly expressed in hepatocellular carcinoma (HCC) tissues and in liver TICs. We find that LncSox4 is required for liver TIC self-renewal and tumour initiation. LncSox4 interacts with and recruits Stat3 to the Sox4 promoter to initiate the expression of Sox4, which is highly expressed in liver TICs and required for liver TIC self-renewal. The expression level of Sox4 correlates with HCC development, clinical severity and prognosis of patients. Altogether, we find that LncSox4 is highly expressed in liver TICs and is required for their self-renewal.

Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy.

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 µM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

The immunogenicity of a novel cytotoxic T lymphocyte epitope from tumor antigen PL2L60 could be enhanced by 4-chlorophenylalanine substitution at position 1.

PIWIL2, a member of PIWI/AGO family, is expressed in germline stem cells and precancerous stem cells, but not in adult somatic cells. PIWIL2 plays an important role in tumor development. It is considered as a cancer­testis antigen (CT80). It has been reported that the spliced fragment of PIWIL2, PL2L60, was widely expressed in cancer cell lines. In this study, HLA-A2-restricted epitopes from PL2L60 were predicted by online tools. To improve the activity of the native epitope, a candidate peptide P281 with potent binding affinity was chosen to investigate the modification strategy. A series of aromatic amino acids were introduced to substitute the first residue of P281. Then, we tested the binding affinity and stability of the peptide analogs and their ability to elicit specific immune responses both in vitro and in vivo. Our results indicated that the cytotoxic T lymphocytes (CTLs) induced by [4-Cl-Phe1]P281 could elicit more potent activities than that of P281 and other analogs. The CTLs induced by this analog could lyze target cells in HLA-A2-restricted and antigen-specific manners. [4-Cl-Phe1]P281 also showed the best resistance against degradation in human serum. In conclusion, the introduction of the unnatural amino acid, 4-Cl-Phe, into the first position could enhance the activity of the native epitope to induce cytotoxic T lymphocytes. It might be a good strategy to modify other promising native epitopes. The novel epitopes identified in this study could be used as novel candidates to the immunotherapy of HLA-A2 positive patients with tumors expressing PL2L60.

Identification of novel T cell epitopes from efflux pumps of Mycobacterium tuberculosis.

Cytotoxic T lymphocytes (CTLs) play an important role in the immunity of Mycobacterium tuberculosis (Mtb) infection. In the present study, the identification of novel CTL epitopes from efflux pumps, Rv1258c and Rv1410c, was reported. Candidate native peptides and their analogues were predicted with prediction programs. Rv1410c-p510 (TLAPQVEPL) and Rv1410c-p510-1Y9V (YLAPQVEPV) showed potent binding affinity and stability towards HLA-A*0201 molecule. In enzyme-linked immunospot (ELISPOT) assay, the CTLs induced from peripheral blood mononuclear cells (PBMCs) by these peptides could release interferon-γ (IFN-γ) in at least one healthy donor (HLA-A*02(+), PPD(+)). In cytotoxicity assay in vitro and in vivo, the CTLs induced by Rv1410c-p510-1Y9V could specifically lyse peptide-loaded T2 cells. This is the first report to identify CTL epitopes from the efflux pumps of Mtb. The novel epitope identified could serve as candidate to the multivalent peptide vaccine against drug-resistant M. tuberculosis.

[Effect of L-arginine on human colon carcinoma cell line LS174 through NO pathway and the mechanism].

OBJECTIVE: To study the effects of L-arginine (L-Arg) on human colon carcinoma cell line LS174 through NO pathway and the mechanism. METHODS: LS174 cells were cultured in the presence of L-Arg at different concentrations for different time. MTT assay was employed to evaluate the cell proliferation, and the cell morphological changes were observed by optical and electron microscopy. The apoptosis of L-Arg-treated cells was observed by the Annexin V/PI staining. The expression levels of VEGF, COX-2, p53, bcl-2 and bax in the cells were determined using Western blotting and immunocytochemical staining. RESULTS: L-Arg promoted the growth of LS174 cells at a low concentration (0.125 mmol/L) and inhibited the cell growth at higher concentrations (0.5, 2, 8, and 32 mmol/L). Under electron microscope, ultrastructual changes in the cytoplasm and nuclei of LS174 cells were observed 48 h after exposure to L-Arg. Some of the cells showed morphological changes characteristic of cell apoptosis such as cell size reduction, condensation and margination of the nuclear chromatin. Low concentration of L-Arg resulted in a cell apoptosis rate of 2.29%, as compared with the rate of 2.84% in the control group; at higher concentrations, L-Arg caused significantly increased cell apoptosis rates to 26.88%, 28.95%, 63.36%, and 84.51%, respectively. In cells treated with a low concentration of L-Arg, the expressions of VEGF and COX-2 were increased as compared with those in the control cells; higher concentrations of L-Arg obviously decreased the expressions of p53 and bcl-2 and increased the expression of bax. CONCLUSION: Low-concentration L-Arg can promote the growth of LS174 cells probably by up-regulating VEGF and COX-2 protein under the influence of NO, the metabolite of L-Arg. The inhibitory effect of high concentrations of L-Arg is probably mediated by inducing cell apoptosis via NO. The mechanism of L-Arg- induced cell apoptosis may be related to the up-regulation of bax protein and the down-regulation of p53 and bcl-2 proteins.

[Expression and significance of membrane skeleton protein 4.1 family in non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Protein 4.1, a component of cell membrane skeleton, plays a role in maintaining the shape and mechanical stability of erythrocytes. Recent researches showed that protein 4.1 may be associated with the development of tumors. This study was to investigate the expression and significance of membrane skeleton protein 4.1 family members (4.1B, 4.1R, 4.1N and 4.1G) in human non-small cell lung cancer (NSCLC). METHODS: The expression of proteins 4.1B, 4.1R, 4.1N and 4.1G in 147 specimens of NSCLC was detected by EnVision plus immunohistochemistry. The correlations of 4.1B, 4.1R, 4.1N and 4.1G expression to clinicopathologic features of NSCLC were analyzed by Wilcoxon rank sum test and Spearman rank correlation analysis. RESULTS: The protein levels of 4.1B, 4.1R and 4.1N were significantly lower in lung squamous cell carcinoma tissues than in adjacent normal tissues (P<0.01). The protein levels of 4.1B, 4.1R, 4.1N and 4.1G were significantly lower in lung adenocarcinoma tissues than in adjacent normal tissues (P<0.05). The protein levels of 4.1B and 4.1G were significantly lower in lung squamous cell carcinoma tissues than in lung adenocarcinoma tissues (P<0.05). Protein 4.1G expression in squamous cell carcinoma was positively correlated to tumor cell differentiation (rs=0.386,P<0.01). In adenocarcinoma, the expression of proteins 4.1B, 4.1N and 4.1G were positively correlated to tumor cell differentiation (rs=0.276, P<0.05; rs=0.248,P<0.05; rs=0.268, P <0.05). The expression of protein 4.1s in squamous cell carcinoma and adenocarcinoma were not related to lymph node metastasis, tumor size, patients'age and sex (P>0.05). CONCLUSIONS: Protein 4.1s are weakly expressed in NSCLC tissues than in adjacent normal tissues. The expression of proteins 4.1B, 4.1N and 4.1G are related to tumor cell differentiation.

Identification of a new broad-spectrum CD8+ T cell epitope from over-expressed antigen COX-2 in esophageal carcinoma.

Cyclooxygenase-2 (COX-2) has been found to be over-expressed in esophageal carcinoma (EC) and it could be considered as a potential tumor-associated antigen (TAA). In the present study, six candidate peptides from COX-2 were firstly predicted and synthesized. Among them, P(479) had the highest affinity and stability toward both HLA-A *0201 and HLA-A *03 molecules and it could significantly promote the IFN-gamma release. The cytotoxic T lymphocytes (CTLs) induced by P(479) could specifically lyse COX-2-expressed EC cell lines, EC-1 (HLA-A3 supertype) and EC-9706 (HLA-A2 supertype). These results suggested that P(479) as a novel broad-spectrum T cell epitope would be very useful in immunotherapy against esophageal carcinoma.

Endomorphins, endogenous opioid peptides, provide antioxidant defense in the brain against free radical-induced damage.

Oxidative stress has been considered to be a major cause of cellular injuries in a variety of chronic health problems, such as carcinogenesis and neurodegenerative disorders. The brain appears to be more susceptible to oxidative damage than other organs. Therefore, the existence of antioxidants may be essential in brain protective systems. The antioxidative and free radical scavenging effects of endomorphin 1 (EM1) and endomorphin 2 (EM2), endogenous opioid peptides in the brain, have been investigated in vitro. The oxidative damage was initiated by a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrocholoride) (AAPH) and hydrogen peroxide (H2O2). The linoleic acid peroxidation, DNA and protein damage were monitored by formation of hydroperoxides, by plasmid pBR 322 DNA nicking assay and single-cell alkaline electrophoresis, and by SDS-polyacrylamide gel electrophoresis. Endomorphins can inhibit lipid peroxidation, DNA strand breakage, and protein fragmentation induced by free radical. Endomorphins also reacted with galvinoxyl radicals in homogeneous solution, and the pseudo-first-order rate constants were determined spectrophotometrically by following the disappearance of galvinoxyl radicals. In all assay systems, EM1 was more potent than EM2 and GSH, a major intracellular water-soluble antioxidant. We propose that endomorphins are one of the protective systems against free radical-induced damage in the brain.