Karyopherin α2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. Emerging evidence suggests that KPNA2 plays a crucial role in oncogenesis and early recurrence. In the ...present study, we evaluated the expression pattern of KPNA2 in 221 hepatocellular carcinoma (HCC) specimens and matching adjacent, non-tumorous tissues (NT) by immunohistochemical assays. We found that nuclear KPNA2 expression was significantly upregulated (30.3 %, 67/221) in HCC tissues; however, no nuclear expression of KPNA2 in NT tissues was observed. A correlation analysis demonstrated that nuclear KPNA2 expression was positively associated with serum AFP level, tumor differentiation, vascular invasion, BCLC stage and early recurrence (all
p
< 0.05). Nuclear KPNA2 expression was associated with a poor prognosis in HCC patients. Univariate and multivariate analyses demonstrated that KPNA2 was an independent prognostic factor for both overall survival (
p
< 0.001) and time to recurrence (
p
< 0.001) in HCC patients. Furthermore, in a validation cohort, nuclear expression of KPNA2 was observed in 16 of 47 (34.0 %) small hepatocellular carcinoma patients. Importantly, the risk of recurrence associated with nuclear KPNA2 expression (9/16, 56.2 %) was significantly higher than the risk associated with an absence of nuclear KPNA2 expression (6/31, 19.3 %;
p
= 0.01). Our results demonstrate that nuclear KPNA2 expression is a poor prognostic biomarker for HCC, especially for early-stage HCC.
Neoadjuvant chemotherapy (NACT) may help reduce the difficulty of surgery and eliminate tiny tumor metastatic foci. It has been reported that 69.4% to 95% of patients with cervical cancer respond to ...NACT. The aim of this study was to evaluate the value of microvessel features in the prediction of response of cervical carcinoma to NACT and its association with the prognosis.
In all, 106 patients (FIGO stage IB2 and IIA2) received NACT followed by radical hysterectomy. Pre-treatment biopsy specimens and post-treatment surgical specimens were stained by immunohistochemistry using CD31 and CD105 antibodies and were counted by quantitative stereology. The correlation between microvessel features microvessel density (MVD) and volume density (Vv) and the clinical response and prognosis were determined using the Mann-Whitney U-test and logistic multivariate analysis.
Of the 106 patients, 74 (69.4%) responded to NACT. The chemotherapeutic response was more favorable in patients with poor pathological grades and tumors larger than 5 cm (P=0.047, P<0.010). According to the pretreatment tumor size and the pathological grade, the patients were divided into six subgroups. In the subgroup of patients with a pretreatment tumor size ≥5 cm and tumors of moderate pathologic grade, the pre-NACT CD31-Vv was higher in NACT nonresponders than in responders (P=0.028). The area under the ROC curve for CD31-Vv was 0.767. In the logistic multivariate analysis, CD31-Vv was not an independent factor that affected the clinical response. The survival analysis showed that although higher post-treatment CD31-Vv was associated with a worse prognosis, Cox proportional hazards regression analysis did not indicate that microvessel features are prognostic predictors (P>0.05). Both pathological grade and invasive depth were independent predictors of survival.
Pre-treatment CD31-Vv could be a predictor of chemosensitivity in one specific subgroup (pre-treatment tumor size ≥5 cm and moderate pathological grade). Post-treatment CD31-Vv is associated with a worse prognosis but is not an independent factor for overall survival.
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found ...in our whole data set?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) 3.19-5.24). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58-3.15), genital (OR 5.24, 95% CI 3.52-8.15) and intercourse (OR 10.65, 95% CI 5.56-23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11-2.27) and phobia (OR 1.41, 95%CI 1.09-1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20-1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02-2.02). Intercourse (OR 3.47, 95%CI 1.66-8.22), use of force and threats (OR 1.95, 95%CI 1.05-3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20-1.64) were significantly associated with recurrent MD.
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
Geometric factor is the key parameter for inversion of particle spectrum in space particle detection. Traditional geometric factor is obtained through the method of numerical calculation with the ...actual structure of the detector as the input condition. The degree of accuracy for data inversion is reduced since traditional geometric factor fails to take into account the physical process of interaction between the particle and substance as well as the influence of factors such as the particle interference between different energy channels on the measurement result. Here we propose an improved geometrical factor calculation method, the concept of which is to conduct actual structural modelling of the detector in the GEANT4 program, consider the process of interaction between the particle and substance, obtain the response function of the detector to particles of different energy channels through the method of Monte Carlo simulation, calculate the influence of contaminated particle on the geometrical factor, and finally get the geometrical factors for different energy channels of the detector. The imrpoved geometrical factor obtained through the method has carried out inversion for the data of high energy protons detector on China＇s FY-3 satellite, the energy spectrum after which is more in line with the power law distribution recognized by space physics. The comparison with the measured result of POES satellite indicates that the FY-3 satellite data are in good accordance with the satellite data, which shows the method may effectively improve the quality of data inversion.
To investigate the molecular mechanisms whereby the Chinese medicinal compound Tongxinluo improves vascular endothelial function through studying the induction of endothelial nitric oxide synthase ...(eNOS) and its upstream signaling pathway.
Hyperhomocysteinemia was induced in Wistar rats by a methionine-rich diet followed by Tongxinluo treatment. The aorta ring was isolated for measuring vascular dilation of aorta and eNOS expression. Human umbilical vein endothelial cells (HUVECs) were transfected with AP-1, NF-κB, HRE or eNOS reporter plasmid followed by Tongxinluo exposure. Expression of the reporter genes was measured by luciferase assay. The level of eNOS was studied by western blot and the nitric oxide content was measured using the nitrate reductase method. HUVECs were also transiently transfected with the dominant negative mutant of HIF-1, PI-3K or Akt to explore the role of HIF and PI-3K/Akt pathway in eNOS induction by Tongxinluo.
Tongxinluo could significantly up-regulate the expression of eNOS in the aortic tissue and improve the endothelium-dependent vasodilation of the aorta ring. Additionally, Tongxinluo at various doses could significantly enhance the expression of HRE and eNOS reporter gene as well as up-regulate the protein level of eNOS. Meanwhile, Tongxinluo caused a dose-dependent increase in the NO content in the supernatant of HUVECs. Suppression of HIF-1 activation by DN-HIF or inhibition of PI-3K/Akt pathway by ΔP85 or DN-Akt both attenuated HRE reporter gene activation and eNOS induction by Tongxinluo.
Tongxinluo, a compound Chinese traditional medicine, up-regulates the expression of eNOS via the PI-3K/Akt/HIF-dependent signaling pathway, thus improving the endothelium-dependent vasodilation.
An efficient and mild protocol for the visible light-induced radical cascade difluoromethylation/cyclization of imidazoles with unactivated alkenes using easily accessible and bench-stable ...difluoromethyltriphenylphosphonium bromide as the precursor of the −CF2H group has been developed to afford CF2H-substituted polycyclic imidazoles in moderate to good yields. This strategy, along with the construction of Csp3–CF2H/C–C bonds, is distinguished by mild conditions, no requirement of additives, simple operation, and wide substrate scope. In addition, the mechanistic experiments have indicated that the difluoromethyl radical pathway is essential for the methodology.
Nucleus accumbens–associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor ...development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1’s N-terminal domain (amino acids 1–130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo. These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.
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