The efficacy and safety of antiangiogenesis tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: A meta-analysis of prospective studies.

BACKGROUND: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events. METHODS: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. RESULTS: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events. CONCLUSION: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies.

Shared genes of polycystic ovary syndrome and sedentary behavior as a novel immune landscape biomarker for endometrial cancer.

Endometrial cancer (EC) is associated with significant risk factors such as polycystic ovarian syndrome (PCOS) and sedentary behavior. In our study, we aim to employ machine learning algorithms to investigate the potential molecular processes that underlie their interaction and explore their respective roles in the diagnosis and immunotherapy of EC. The GEO database provides access to microarray data, which was utilized in this study to identify gene expression modules associated with PCOS and sedentary behavior, using weighted gene expression network analysis (WGCNA). Cluego software was then employed to investigate the energy enrichment of shared pathways in both PCOS and sedentary individuals, and differential gene analysis was used to confirm another two databases. The miRNAs-mRNAs controlled network was constructed to verify the pathway. The immune-related factors of the shared pathway in EC were then analyzed. Finally, to validate our findings, we conducted cell experiments using EC cell lines (AN3CA, KLE, Ishikawa, RL95-2, and HEC-1A). We found that increased intracellular aromatic compound anabolism is a common feature of both PCOS and sedentary individuals. We then developed a disease pathway model that was based on the common genetic characteristics of PCOS and sedentary behavior. We utilized pathway typing in EC samples and found a significant survival difference between the two subgroups, with the upregulated expression type exhibiting an immune-hot phenotype. Finally, the experimental results confirmed the expression of the hub gene (NAA15) in EC. The findings of our study suggest that genes related to the intracellular aromatic compound metabolic pathway can be used for immunotherapy of EC.

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. RESULTS: In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8+/CD4+ ratio on day 14 indicated a longer OS (p = 0.010). CONCLUSIONS: Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. TRIAL REGISTRATION: NCT04766320, Jan 04, 2021.

Umbilical cord blood-derived neutrophils possess higher viability than peripheral blood derived neutrophils.

Neutrophils, a primary type of immune cell, play critical roles in numerous biological processes. Both umbilical cord blood (UCB) and peripheral blood are rich in neutrophils. UCB is more abundant than peripheral blood, with cells generally at a more immature stage. However, comparative data between these two cell sources is lacking. This study aims to elucidate differences between UCB-derived neutrophils (UCBN) and peripheral blood-derived neutrophils (PBN). UCBN and PBN were isolated from fresh human umbilical cord blood and peripheral blood, respectively. Transcriptomic profiling was performed and compared against neutrophil RNA from three different donors. Bioinformatics analysis was employed to compare cell phenotypes. A cytokine cocktail (IFN-ß, IFN-γ, and LPS) was used to activate UCBN and PBN in vitro. A united multi-omic approach, combining transcriptomic and proteomic analysis, was followed by experimental validation through flow cytometry, cell killing assays, and proteome profiler array to verify cell functions. Transcriptomic analysis revealed that the most upregulated genes in freshly isolated umbilical cord blood neutrophils (UCBN) compared to peripheral blood neutrophils (PBN) predominantly involve neutrophil activation and cell-killing functions. Validation through flow cytometry and cell-killing experiments demonstrated that highly viable UCBN exhibited significantly stronger ovarian tumor cell-killing activity in vitro compared to PBN. Both transcriptomic and proteomic analyses indicated that the primary upregulated genes in activated UCBN are chiefly involved in biological processes related to the regulation of cytokine secretion. Integrative multi-omic analysis, including a proteome profiler array, confirmed that UCBN indeed secrete elevated levels of cytokines. In conclusion: UCBN shows higher viability and cellular activity compared with PBN, particularly in tumor cell-killing and cytokine secretion.

Prognostic differences in sepsis caused by gram-negative bacteria and gram-positive bacteria: a systematic review and meta-analysis.

BACKGROUND: Bacteria are the main pathogens that cause sepsis. The pathogenic mechanisms of sepsis caused by gram-negative and gram-positive bacteria are completely different, and their prognostic differences in sepsis remain unclear. METHODS: The PubMed, Web of Science, Cochrane Library, and Embase databases were searched for Chinese and English studies (January 2003 to September 2023). Observational studies involving gram-negative (G (-))/gram-positive (G (+)) bacterial infection and the prognosis of sepsis were included. The stability of the results was evaluated by sensitivity analysis. Funnel plots and Egger tests were used to check whether there was publication bias. A meta-regression analysis was conducted on the results with high heterogeneity to identify the source of heterogeneity. A total of 6949 articles were retrieved from the database, and 45 studies involving 5586 subjects were included after screening according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-seven high-quality studies and 18 moderate-quality studies were identified according to the Newcastle‒Ottawa Scale score. There was no significant difference in the survival rate of sepsis caused by G (-) bacteria and G (+) bacteria (OR 0.95, 95% CI 0.70-1.28). Subgroup analysis according to survival follow-up time showed no significant difference. The serum concentrations of C-reactive protein (CRP) (SMD = 0.39, 95% CI 0.02-0.76), procalcitonin (SMD = 1.95, 95% CI 1.32-2.59) and tumor necrosis factor-alpha (TNF-α) (MD = 0.31, 95% CI 0.25-0.38) in the G (-) bacterial infection group were significantly higher than those in the G (+) bacterial infection group, but there was no significant difference in IL-6 (SMD = 1.33, 95% CI - 0.18-2.84) and WBC count (MD = - 0.15, 95% CI - 0.96-00.66). There were no significant differences between G (-) and G (+) bacteria in D dimer level, activated partial thromboplastin time, thrombin time, international normalized ratio, platelet count, length of stay or length of ICU stay. Sensitivity analysis of the above results indicated that the results were stable. CONCLUSION: The incidence of severe sepsis and the concentrations of inflammatory factors (CRP, PCT, TNF-α) in sepsis caused by G (-) bacteria were higher than those caused by G (+) bacteria. The two groups had no significant difference in survival rate, coagulation function, or hospital stay. The study was registered with PROSPERO (registration number: CRD42023465051).

[Silencing of SMAD family member 3 promotes M2 polarization of macrophages and the expression of SMAD7 in rheumatoid arthritis].

Objective To investigate the effect of SMAD family member 3(SMAD3) silenced by small interfering RNA (siRNA) on macrophage polarization and transforming growth factor ß1 (TGF-ß1)/ SMAD family signaling pathway in rheumatoid arthritis (RA). Methods RA macrophages co-cultured with rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were used as a cell model. TGF-ß1 was used to stimulate macrophages, and SMAD3-specific siRNA (si-SMAD3) and negative control siRNA (si-NC) were transfected into human RA macrophages co-cultured in TranswellTM chamber. The expression of SMAD3 mRNA was detected by real-time fluorescence quantitative PCR, and the expression of TGF-ß1, SMAD3 and SMAD7 protein was detected by Western blot analysis. The contents of TGF-ß1 and IL-23 in cell culture supernatant were determined by ELISA. Cell proliferation was detected by CCK-8 assay. TranswellTM chamber was used to measure cell migration. Results Compared with the model group and the si-NC group, the expression of TGF-ß1, SMAD3 mRNA and protein in RA macrophages decreased significantly after silencing SMAD3. In addition, the secretion of IL-23 decreased significantly, and the cell proliferation activity and cell migration were inhibited, with high expression of SMAD7. Conclusion Knockdown of SMAD3 can promote M2 polarization and SMAD7 expression in RA macrophages.

MUC16 stimulates neutrophils to an inflammatory and immunosuppressive phenotype in ovarian cancer.

BACKGROUND: MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored. METHODS: The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro. RESULTS: The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b+, CD66b+, and ICAM-1+ neutrophils were significantly increased, while the proportion of CXCR4+ neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1ß, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro. CONCLUSION: MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.

Identification of Expression Pattern and Clinical Significance of the Small Cajal Body-specific RNA SCARNA16 in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: For high morbidity and mortality, hepatocellular carcinoma (HCC) becomes a major health issue worldwide. Nowadays, numerous non-coding RNAs (ncRNAs) are known to regulate the occurrence and pathogenesis of tumors. Some ncRNAs have also been developed as tumor biomarkers and therapeutic targets. However, the potential function of the small Cajal body-specific RNA (scaRNA) SCARNA16, a newly identified ncRNA, remains to be explored in HCC. METHODS: In both HCC cell lines and specimens from 120 enrolled patients, the expression values of SCARNA16 were detected. We divided patients into SCARNA16 high and low expression subgroups, and then analyzed the difference of various clinical characteristics and prognosis data between subgroups. RESULTS: Compared to paired controls, SCARNA16 was significantly down-regulated in HCC cell lines and clinical specimens (p<0.01). Besides, HCC patients with lower SCARNA16 expression commonly presented with larger and more tumor lesions, more vessel carcinoma emboli, more capsular invasion and higher TNM stages (p<0.05). Moreover, SCARNA16 expression was negatively correlated with postoperative prognosis of HCC patients in 5-year follow-up, including tumor-free survival (TFS) (median time of low vs. high subgroups: 14 vs. 48 months, p=0.006) and overall survival (OS) (median time of low vs. high subgroups: 39 vs. 52 months, p=0.001). Besides, SCARNA16 acted as an independent prognostic biomarker in TFS (hazard ratio [HR]: 0.578, 95% CI: 0.345-0.969, p=0.038) and OS (HR: 0.366, 95% CI: 0.178-0.752, p=0.006). CONCLUSIONS: Low expression patterns of SCARNA16 remarkably associated with severe clinical status and poor survival of patients, suggesting that SCARNA16 possesses potency as a novel biomarker for HCC.

[Mechanism of Xinfeng Capsules improving rheumatoid arthritis based on CD19~+B cells regulating FAK/CAPN/PI3K pathway].

To observe the effect of Xinfeng Capsules on rheumatoid arthritis (RA) B lymphocytes,inflammatory mediators,FAK/CAPN/PI3K pathway,in order to explore the mechanism of Xinfeng Capsules in improving clinical symptoms of RA.Joint and systemic symptoms of RA patients were observed,and laboratory indicators[hemoglobin (HGB),platelet count (PLT),erythrocyte sedimentation (ESR),immunoglobulin (Ig) G,Ig A,Ig M,rheumatoid factor (RF),anti-cyclic citrulline antibody (CCP-AB),C-reactive protein (CRP)]were detected.ELISA was used to detect serum interleukin (IL)-1ß，IL-10,IL-33,chemokine 5 (CCL5),and vascular endothelial growth factor (VEGF).CD3~-CD19~+B cells were measured by flow cytometry.Western blot was used to detect FAK,p-FAK,CAPN,PI3K protein.The results showed that Xinfeng Capsules could significantly alleviate RA joint and systemic symptoms and improve clinical efficacy.And Xinfeng Capsules could increase HGB,decrease PLT,CCP-AB,CRP,ESR index,upregulate IL-10 expression,and down-regulate IL-1ß，IL-33,CCL5,VEGF,CD3~-CD19~+B cells,FAK,p-FAK,CAPN,PI3K expressions (P<0.01).Based on the above results,Xinfeng Capsules may reduce the expression of CD3~-CD19~+,regulate the balance of inflammatory cytokines and chemokines,inhibit abnormal activation of FAK/CAPN/PI3K pathway,and improve clinical symptoms of RA.

Downregulation of snoRNA SNORA52 and Its Clinical Significance in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive tumors in the world while the accuracy of the present tests for detecting HCC is poor. A novel diagnostic and prognostic biomarker for HCC is urgently needed. Overwhelming evidence has demonstrated the regulatory roles of small nucleolar RNA (snoRNA) in carcinogenesis. This study is aimed at analyzing the expression of a snoRNA, SNORA52, in HCC and exploring the correlation between its expression and various clinical characteristics of HCC patients. By using quantitative real-time PCR, we found that SNORA52 was downregulated in HCC cell lines (P < 0.05) and HCC tissues (P < 0.001). Correlation analysis showed that the expression of SNORA52 was obviously associated with tumor size (P = 0.011), lesion number (P = 0.007), capsular invasion (P = 0.011), tumor differentiation degree (P = 0.046), and TNM stage (P = 0.004). The disease-free survival (DFS) and overall survival (OS) analysis showed that patients with lower SNORA52 expression had a worse prognosis (P < 0.001). Univariate and multivariate Cox regression analysis showed that SNORA52 expression was a completely independent prognostic factor to predict DFS (P = 0.009) and OS (P = 0.012) of HCC patients. Overall, our findings showed SNORA52 expression levels were downregulated in HCC tissues and correlated with multiple clinical variables, and SNORA52 was an independent prognostic factor for HCC patients, which suggested that SNORA52 could function as a potential diagnostic and prognostic biomarker for HCC patients.

Identification of snoRNA SNORA71A as a Novel Biomarker in Prognosis of Hepatocellular Carcinoma.

BACKGROUND: Small nucleolar RNAs (snoRNAs) have been proved to play important roles in various cellular physiological process. Recently, dysregulation of snoRNA SNORA71A has been found involved in tumorigenesis of various malignant cancers. However, the emerging effects of SNORA71A in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we aimed to explore the SNORA71A expression and its underlying significance in HCC. METHODS: Expression of SNORA71A in cell lines and clinical specimens was measured by quantitative real-time PCR. Then, all enrolled HCC patients were divided into low and high SNORA71A expression subgroups and then they were compared in the aspects of clinical features as well as survival outcome by respective statistical analysis methods. RESULTS: SNORA71A was significantly downexpressed in SK-HEP-1 (P = 0.001), Huh-7 (P < 0.001), Hep3B (P < 0.001), and clinical HCC specimens (P = 0.006). Comparing the clinical features between SNORA71A expression subgroups, it showed that low SNORA71A expression was significantly associated with large tumor diameter, multiple lesions, capsular invasion, bad tumor differentiation, and TNM stage (P < 0.05). Furthermore, it was found that HCC patients with lower SNORA71A expression had higher risk in postoperative tumor relapse (median time: 9.5 vs. 35.2 months; low vs. high; P < 0.001) and poor overall survival (median time: 36.8 vs. 52.9 months; low vs. high; P < 0.001). Besides, SNORA71A expression served as independent risk factors for tumor-free (HR = 0.450; 95% CI [0.263-0.770]; P = 0.004) and long-term survival (HR = 0.289; 95% CI [0.127-0.657]; P = 0.003). CONCLUSIONS: Our study for the first time demonstrated that downregulation of SNORA71A could serve as a novel biomarker for clinical assessment and prognostic prediction of HCC patients.

Down-regulation of small nuclear RNA (snRNA) RNU5E-1 in hepatocellular carcinoma presents with vital clinical significance.

BACKGROUND: For lack of accurate diagnosis and ideal prognosis assessment, hepatocellular carcinoma (HCC) has become the fourth cancers-related death malignant diseases. Small nuclear RNAs (snRNAs) have been investigated as a new class of regulators associated with pathogenesis and clinical evaluation of tumors such as HCC. As for RNU5E-1, one newly identified snRNA, may have similar functions. However, the relationship between RNU5E-1 expression and HCC tumorigenesis remains unclear. METHODS: The relative RNU5E-1 expression was measured in several HCC cell lines and HCC tissues of 100 patients using quantitative real-time PCR. All patients were grouped according to individual RNU5E-1 expression. Then, the potential association between RNU5E-1 expression in HCC clinical characteristics and prognostic information of patients was evaluated. RESULTS: Compared to human normal hepatocyte cell line QSG-7701, the RNU5E-1 expression in HCC cell lines (fold change: SK-HEP-1, 0.417; Hep 3B, 0.313; Huh-7, 0.189) were significantly down-regulated (P<0.05). Similarly, its expression levels were remarkably lower in HCC tissue than that in corresponding adjacent liver tissues (average fold change: 0.322, P=0.002). Besides, the expression level of RNU5E-1 was remarkably related to tumor size, vessel carcinoma embolus, differentiation level, TNM stages and tumor recurrence rate as well as long-term survival in HCC patients (P<0.05). Moreover, in Kaplan-Meier and Cox regression analysis, RNU5E-1 expression was remarkably correlated to postoperative tumor-free as well as long-term survival in HCC patients as independent factors (P<0.05). CONCLUSIONS: The research revealed that RNU5E-1 was down-regulated in HCC and it could be one of indicators for diagnosis and prognostic prediction of HCC patients.

Revealing the clinical significance and prognostic value of small nucleolar RNA SNORD31 in hepatocellular carcinoma.

BACKGROUND: For lack of accurate early diagnosis and prognostic assessment, hepatocellular carcinoma (HCC) becomes severe challenge with the fourth cancer-related mortality. Recently, non-coding RNA (ncRNA) was identified to make functions in progression of various tumors. Among that, a novel ncRNA, small nucleolar RNA C/D box 31 (SNORD31) was suggested in previous study to function as potential tumor suppressing role. In the present study, we aimed to investigate the expression patterns and clinical significance of SNORD31 in HCC. METHODS: SNORD31 expression was calculated in HCC cell lines as well as clinical specimens by RT-PCR. HCC patients were subdivided into high and low SNORD31 expression groups and their clinical characteristics were compared. Besides, the association between SNORD31 expression and postoperative prognosis was evaluated using Kaplan-Meier and Cox regression analysis. RESULTS: Compared with corresponding normal reference, expression levels of SNORD31 were significantly down-regulated in both HCC cell lines and clinical specimens (P<0.01). Moreover, low SNORD31 expression was remarkably correlated with large tumor diameter, high incidence of vessel carcinoma embolus and capsular invasion, severe tumor differentiation and tumor-node-metastasis (TNM) stage (P<0.05). In the following analysis, HCC patients with low SNORD31 expression were independently inclined with poor tumor-free (median time: 9.17 vs 48.8 months, low vs high, P<0.001) as well as long-term survival (LTS; median time: 40.26 vs 55.41 months, low vs high, P=0.002). CONCLUSIONS: The ncRNA SNORD31 was proved to be commonly down-regulated in HCC and was independently associated with multiple malignant characteristics and long-term prognosis of HCC patients, which implied that SNORD31 possessed potential as a novel HCC biomarker.

Down-regulation of Long Non-coding RNA LINC01554 in Hepatocellular Cancer and its Clinical Significance.

Background: For high morbidity rate but lack of early accurate screening, hepatocellular cancer (HCC) manifests as the fourth leading cause of cancer related death worldwide. Accumulating evidence demonstrated that a series of long noncoding RNA (lncRNA) have strong association with pathogenesis and clinical evaluation of HCC. LINC01554, one kind of lncRNA, has been found specifically enriched in liver tissue. However, the relationship between LINC01554 expression and HCC tumorigenesis remains unclear. Methods: The relative LINC01554 expression was measured in HCC tissues of 138 patients and several HCC cell lines using quantitative real-time PCR. Patients were grouped according to individual LINC01554 expression. Then, the potential association between LINC01554 expression in HCC tissues and clinical characteristics as well as prognostic information of patients was evaluated. Results: Compared to correspongding adjacent liver tissues, the LINC01554 expression in HCC was significantly down-regulated (P=0.001). And its expression levels in HCC cell lines were also remarkably lower than that in normal human hepatocyte cell line (P<0.001). Besides, the expression level of LINC01554 was significantly related to tumor size, multiple lesions, TNM stages, tumor recurrence rate as well as long-term survival in HCC patients (P<0.05). Conclusion: The research revealed that LINC01554 was down-regulated in HCC and it could be used for the accurate diagnosis and prognostic prediction of HCC patients.

Paired eye-control study of unilateral opaque bubble layer in femtosecond laser assisted laser in situ keratomileusis.

AIM: To investigate the predictive factors of the opaque bubble layer (OBL) compared to the fellow eye of same patients in FS200 femtosecond laser assisted laser in situ keratomileusis (FS-LASIK). METHODS: This study consisted of 60 consecutive patients (120 eyes) with unilateral OBL during FS-LASIK. Eyes were divided into OBL (the OBL eyes) and OBL-free groups (the fellow eyes) based on the occurrence of OBL. The preoperative demographic data, refraction, keratometry, corneal astigmatism, pachymetry, intraocular pressure and intraoperative data including the outlet location of gas diffusing canal were collected. Conditional logistic regression analysis was performed to find the associated factors with OBL in the two groups by determining odds ratios (OR) and 95%CI. RESULTS: The preoperative demographic data, mean spherical errors, mean K value, suction time, intraocular pressure and central cornea thickness were not significantly different between the two groups. The outlet location of gas diffusing canal (P<0.01, OR 7.16, 95%CI 2.53-20.32) and the corneal astigmatism (P=0.013, OR 0.13, 95%CI 0.03-0.65) were significantly associated with the incidence of OBL by multivariate logistic regression analysis. Visual acuity, efficacy, and safety were comparable between the two groups two months after surgery except for a slightly lower predictability value for the hard OBL eyes. CONCLUSION: The reduction of the incidence of OBL is obvious when the outlet of gas diffusing canal located at the posterior border of the corneoscleral limbus. This is probably consequent to more effectiveness of gas diffusing canal. Corneal astigmatism is also an independent protective factor for OBL formation.

Staging Surgery for The Treatment of Aortic Arch Aneurysm Combined with Aberrant Bilateral Subclavian Artery, Persistent Left Superior Vena Cava and Airway Compression: A Case Report.

BACKGROUND: To describe staging surgery for the treatment of a patient with aortic arch aneurysm combined with aberrant bilateral subclavian artery, persistent left superior vena cava (PLSVC), and airway compression. CASE REPORT: A 42-year-old female was hospitalized for aortic arch aneurysm involving aberrant bilateral subclavian artery, PLSVC, and airway compression. The patient's aneurysm was successfully treated by stage I surgery, including total aortic arch replacement and stented elephant trunk procedure and stage II surgery, including tracheal stenting and tracheotomy. Aortic CTA examination showed an unobstructed lumen and a good stent position without tracheal stent migration. Regular postoperative follow-up showed no complications, such as dyspnea, cough, and sputum, or other discomfort symptoms. CONCLUSIONS: Total aortic arch replacement, elephant trunk surgery, and second-stage tracheal stent surgery are effective and safe for the treatment of aortic arch aneurysm combined with aberrant bilateral subclavian artery, PLSVC, and airway compression.

NBGNU: a hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance.

Aim: A hypoxia-activated combi-nitrosourea prodrug, N-(2-chloroethyl)-N'-2-(2-(4-nitrobenzylcarbamate)-O6-benzyl-9-guanine)ethyl-N-nitrosourea (NBGNU), was synthesized and evaluated for its hypoxic selectivity and anticancer activity in vitro. Results: The prodrug was designed as a tripartite molecule consisting of a chloroethylnitrosourea pharmacophore to induce DNA interstrand crosslinks (ICLs) and an O6-benzylguanine analog moiety masked by a 4-nitrobenzylcarbamate group to induce hypoxia-activated inhibition of O6-alkylguanine-DNA alkyltransferase. NBGNU was tested for hypoxic selectivity, cytotoxicity and DNA ICLs ability. The reduction product amounts, cell death rates and DNA ICL levels induced by NBGNU under hypoxic conditions were all significantly higher than those induced by NBGNU under normoxic conditions. Conclusion: The tripartite combi-nitrosourea prodrug exhibits desirable tumor-hypoxia targeting ability and abolished chemoresistance compared with the conventional chloroethylnitrosoureas.

Hepatocyte-generated 27-hydroxycholesterol promotes the growth of melanoma by activation of estrogen receptor alpha.

Cholesterol plays an important role in maintaining normal physiological function of human body. However, excessive intake will induce a series of diseases including cancer. For melanoma, the relationship between hypercholesterolemia and its incidence remains unknown. The cholesterol metabolite 27-hydroxy cholesterol (27-HC) catalyzed by CYP27A1 has been reported to activate estrogen receptor (ER). As studies have indicated that melanoma expresses ER, we designed experiments to explore whether 27-HC could link hypercholesterolemia and melanoma. In this study, hepatocyte-specific CYP27A1-/- mice were generated by CRISPR/Cas9 technology. The results revealed that high-cholesterol diet induced metabolism disorder and promoted the melanoma growth through 27-HC. Further study found that 27-HC promoted the growth of melanoma cells by activating ERα and eliciting the AKT and MAPK signaling pathway. This study puts forward the important role of 27-HC in the development of melanoma for the first time, links hypercholesterolemia with melanoma progression. The research also provides the rationale for the use of tamoxifen in melanoma therapy. The levels of 27-HC in blood could act as a novel biomarker for tamoxifen treatment in melanoma patients.