Overexpression of cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma.

BACKGROUND: Cystatin SN is a secreted protein and a cysteine proteinase inhibitor. It has been considered to be a tumor marker for gastrointestinal tract cancer in several functional researches. However, the clinicopathological and prognostic significance of Cystatin SN expression in esophageal squamous cell carcinoma (ESCC) has not been elucidated. METHODS: In our study, the expression of Cystatin SN was detected in 209 surgically resected ESCC tissues and 170 peritumoral normal esophageal mucosae by immunohistochemistry. The prognostic significance of Cystatin SN expression was analysed with Kaplan-Meier plots and the Cox proportional hazards regression models. RESULTS: The results showed that the immunostaining of Cystatin SN in ESCC tissues was less intense than that in the normal control tissue (P < 0.001). Compared with patients with low tumoral Cystatin SN expression, ESCC patients with tumors high-expression Cystatin SN exhibited increased disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively). Furthermore, the expression level of Cystatin SN could further stratify the ESCC patients by survival (DFS and OS) in the stage II subgroup (P < 0.001 and P < 0.001, respectively). Multivariate analyses showed that Cystatin SN expression, N status and differentiation were independent and significant predictors of survival. CONCLUSIONS: We concluded that ESCC patients whose tumors express high levels of Cystatin SN have favourable survival compared with those patients with low Cystatin SN expression. Tumoral Cystatin SN expression may be an independent predictor of survival for patients with resectable ESCCs.

Acupuncture for Quality of Life in Gastric Cancer Patients Undergoing Adjuvant Chemotherapy.

CONTEXT: Patients with gastric cancer experience health-related quality of life (HRQOL) decline during adjuvant chemotherapy following gastrectomy. OBJECTIVES: This pilot study aimed to evaluate the preliminary effect and feasibility of electro-acupuncture (EA) for HRQOL and symptom burden in these patients. METHODS: In this open-label, multicenter, parallel controlled trial, gastric cancer patients who planned to receive adjuvant chemotherapy were randomly assigned to receive high-dose EA (seven times each chemotherapy cycle for three cycles), low-dose EA (three times each chemotherapy cycle), or usual care only. The acupoints prescription consisted of bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points. Patients completed the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) weekly, and the Edmonton Symptom Assessment System (ESAS). The primary outcome was the difference among the groups on the gastric cancer subscale (GaCS) of the FACT-Ga. RESULTS: Of the 66 randomized patients, 58 were analyzed according to intention-to-treat principle, and 45 were in the per-protocol set (PPS). The average scores in PPS of GaCS were 52.12±9.71, 51.85±12.36, and 45.37±8.61 in high-dose EA, low-dose EA, and control groups, respectively. EA was significantly associated with improved average GaCS scores when compared with control group (51.98±10.91 vs. 45.37±8.61, P = 0.039). EA treatment also produced ESAS relief at the end of intervention (14.36 ± 12.28 vs. 23.91 ± 15.52, P = 0.027). Participants in EA groups had fewer grade ≥3 leukopenia (0% vs. 15.79%, P = 0.031) and neutropenia (2.56% vs. 26.31%, P = 0.012). CONCLUSION: EA showed promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

Blood neutrophil-to-lymphocyte ratio predicts survival in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization.

PURPOSE: To evaluate whether the neutrophil-to-lymphocyte ratio (NLR) predicts survival in patients with unresectable hepatocellular carcinoma (HCC) before and after transarterial chemoembolization treatment. MATERIALS AND METHODS: Clinical and laboratory data for 145 consecutive patients undergoing transarterial chemoembolization for unresectable HCC during 2001-2004 were analyzed retrospectively. The NLR was recorded before and 3 days after treatment. RESULTS: The pretreatment mean NLR was 3.3; 59 (40.7%) patients had an elevated NLR (≥ 3.3). The median survival of patients with a high NLR was 8 months (range 1-28 months) compared with 12 months (range 2-41 months) for patients with a normal NLR; a significant difference was found in overall survival (log-rank test, P = .001). The NLR was increased in 127 (87.6%) patients after transarterial chemoembolization and was decreased in 18 patients; the increase indicated better outcomes (log-rank test, P = .006). Age (≥ 49 y), high NLR, decreased NLR after treatment, large tumor (≥ 5 cm), vascular invasion, and elevated serum α-fetoprotein (AFP) level all were predictors of poor survival. Multivariate analysis showed that a high NLR (P = .041) and vascular invasion (P = .040) were independent factors for predicting worse survival. CONCLUSIONS: A high NLR independently predicts poor survival in patients with unresectable HCC undergoing transarterial chemoembolization treatment, and an increased NLR indicates a better outcome than a decreased NLR for patients after transarterial chemoembolization.

Inhibitory effect of modified citrus pectin on liver metastases in a mouse colon cancer model.

AIM: To discuss the expression of glactin-3 in liver metastasis of colon cancer and its inhibition by modified citrus pectin (MCP) in mice. METHODS: Seventy-five Balb/c mice were randomly divided into negative control group (n = 15), positive control group (n = 15), low MCP concentration group (n = 15), middle MCP concentration group (n = 15) and high MCP concentration group (n = 15). CT26 colon cancer cells were injected into the subcapsule of mouse spleen in positive control group, low, middle and high MCP concentrations groups, except in negative control, to set up a colon cancer liver metastasis model. The concentration of MCP in drinking water was 0.0%, 0.0%, 1.0%, 2.5% and 5.0% (wt/vol), respectively. Liver metastasis of colon cancer was observed after 3 wk. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of galectin-3 in serum. Expression of galectin-3 in liver metastasis was detected by immunohistochemistry. RESULTS: Except for the negative group, the percentage of liver metastasis in the other 4 groups was 100%, 80%, 73.3% and 60%, respectively. The number of liver metastases in high MCP concentration group was significantly less than that in positive control group (P = 0.008). Except for the negative group, the median volume of implanted spleen tumor in the other 4 groups was 1.51 cm(3), 0.93 cm(3), 0.77 cm(3) and 0.70 cm(3), respectively. The volume of implanted tumor in middle and high MCP concentration groups was significantly smaller than that in positive control group (P = 0.019; P = 0.003). The concentration of serum galectin-3 in positive control and MCP treatment groups was significantly higher than that in the negative control group. However, there was no significant difference between them. Except for the negative control group, the expression of galectin-3 in liver metastases of the other 4 groups showed no significant difference. CONCLUSION: Expression of galetin-3 increases significantly in liver metastasis of colon cancer, which can be effectively inhibited by MCP.

Enhanced circulating transforming growth factor beta 1 is causally associated with an increased risk of hepatocellular carcinoma: a mendelian randomization meta-analysis.

The aim of this study was to test the causal association between circulating transforming growth factor beta 1 (protein: TGF-ß1 and coding gene: TGFB1) and hepatocellular carcinoma by choosing TGFB1 gene C-509T polymorphism as an instrument in a Mendelian randomization (MR) meta-analysis. Ten English articles were identified for analysis. Two authors independently assessed each article and abstracted relevant data. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were synthesized under a random-effects model. Overall, the association of C-509T polymorphism with hepatocellular carcinoma was negative, but its association with circulating TGF-ß1 was statistically significant, with a higher concentration observed in carriers of the -509TT genotype (WMD, 95% CI, P: 1.72, 0.67-2.78, 0.001) and -509TT/-509TC genotypes (WMD, 95% CI, P: 0.98, 0.43-1.53, < 0.001). In subgroup analysis, C-509T polymorphism was significantly associated with hepatocellular carcinoma in population-based studies under homozygous-genotype (OR, 95% CI, P: 1.74, 1.08-2.80, 0.023) and dominant (OR, 95% CI, P: 1.48, 1.01-2.17, 0.047) models. Further MR analysis indicated that per unit increase in circulating TGF-ß1 was significantly associated with a 38% (95% CI: 1.03-4.65) and 49% (95% CI: 1.01-6.06) increased risk of hepatocellular carcinoma under homozygous-genotype and dominant models, respectively. Conclusively, based on a MR meta-analysis, our findings suggest that enhanced circulating TGF-ß1 is causally associated with an increased risk of hepatocellular carcinoma.

Analysis of ERCC1, BRCA1, RRM1 and TUBB3 as predictors of prognosis in patients with non-small cell lung cancer who received cisplatin-based adjuvant chemotherapy: A prospective study.

Although adjuvant platinum-based chemotherapy has been demonstrated to improve survival in patients with completely resected non-small cell lung cancer (NSCLC), individualized approaches to therapy are urgently required to improve the treatment efficacy and reduce unnecessary toxicity. It was hypothesized in the present study that the protein levels of excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase M1 (RRM1) and class III ß-tubulin (TUBB3) may influence the therapeutic effect of adjuvant cisplatin-based chemotherapy. The expression of ERCC1, BRCA1, RRM1 and TUBB3 in tissues obtained from 84 patients with NSCLC was analyzed in the present non-interventional study by immunohistochemistry prior to adjuvant chemotherapy. All patients received adjuvant cisplatin-based chemotherapy. The primary endpoint in the present study was disease free survival (DFS). Out of the 84 tumors, the expression of ERCC1, BRCA1, RRM1 and TUBB3 was identified in 46 (55%), 11 (13%), 73 (87%) and 76 (90%) tissues, respectively. A beneficial response to adjuvant cisplatin-based chemotherapy in DFS was associated with the absence of the expression of ERCC1 [hazard ratio (HR), 2.166; 95% confidence interval (CI), 1.049-4.474; P=0.037] and BRCA1 (HR, 2.419; 95% CI, 1.127-5.193; P=0.023), but not with the expression status of RRM1 (HR, 0.568; 95% CI, 0.234-1.379; P=0.212) or TUBB3 (HR, 1.874; 95% CI, 0.448-7.842; P=0.39). In addition, patients lacking the expression of ERCC1 and BRCA1 benefited more from adjuvant cisplatin-based chemotherapy compared with patients that expressed either ERCC1 or BRCA1 (HR, 3.102; 95% CI, 1.343-7.163; P=0.008). The expression of ERCC1 and BRCA1 was significantly associated with the DFS time in patients with NSCLC treated with adjuvant cisplatin-based chemotherapy, respectively. The combination of the ERCC1 and BRCA1 expression levels may be a promising prognostic prediction for adjuvant cisplatin-based chemotherapy.

[Efficacy of complex Hongyibuxue oral solution and ferrous sulfate for iron deficiency anemia].

OBJECTIVE: To observe the efficacy of complex Hongyibuxue oral solution in the treatment of iron deficiency anemia (IDA). METHODS: One hundred patients of IDA were randomly divided into test group or control group (50 cases each). Patients in the test group took complex Hongyibuxue oral solution and those in the control group took ferrous sulfate in a treatment course of 4 weeks. RESULTS: Hemoglobin, serum iron and serum ferritin in the test group rose faster than those in control group (P<0.05). The improvement of the anemic symptoms and tolerance of patients to complex Hongyibuxue oral solution in the test group were much better than ferrous sulfate. CONCLUSION: The therapeutic effect of and tolerance of patients to complex Hongyibuxue oral solution are better than ferrous sulfate in the treatment of IDA.

High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis.

To analyze the expression of the transforming acidic coiled-coil protein 3 (TACC3) in esophageal squamous cell carcinoma (ESCC) samples, and to identify whether TACC3 can serve as a biomarker for the diagnosis and prognosis of ESCC, qPCR, western blotting and immunohistochemistry staining (IHC) were utilized to detect the expression of TACC3. Furthermore, cell growth, colony formation, migration ability and the epithelial-mesenchymal transition markers of ESCC cells in which TACC3 were knocked-down were measured. The mRNA and protein levels of TACC3 were higher in ESCC specimens compared to non-tumorous esophageal epithelial tissues. IHC results revealed TACC3 expression was significantly correlated to differentiation (p = 0.017) and lymphoid nodal status (p = 0.028). The patients with high-expression of TACC3 had a significantly poor prognosis compared to those of low-expression (p = 0.017), especially in the patients at stages I-II (p = 0.028). Multivariate analysis indicated that TACC3 expression was an independent prognostic factor for ESCC patients (p = 0.025). Knockdown of TACC3 inhibited the ability of cell proliferation, colony formation and migration. This study first identifies TACC3 not only as a useful biomarker for diagnose and prognosis of ESCC, but also as a potential therapeutic target for patients with ESCC.

The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution.

More than 90% of lung cancers are caused by cigarette smoke and air pollution, with polycyclic aromatic hydrocarbons (PAHs) as key carcinogens. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China, attributed to smoky coal combustion-generated PAH pollution. Here, we screened for abnormal inflammatory factors in non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used, and found that a chemokine CXCL13 was overexpressed in 63/70 (90%) of Xuanwei NSCLCs and 44/71 (62%) of smoker and 27/60 (45%) of non-smoker CR patients. CXCL13 overexpression was associated with the region Xuanwei and cigarette smoke. The key carcinogen benzo(a)pyrene (BaP) induced CXCL13 production in lung epithelial cells and in mice prior to development of detectable lung cancer. Deficiency in Cxcl13 or its receptor, Cxcr5, significantly attenuated BaP-induced lung cancer in mice, demonstrating CXCL13's critical role in PAH-induced lung carcinogenesis.

Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors.

Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 36/64 (56.3%) of non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting molecules including a natural compound 6-O-angeloylplenolin (6-OAP). 6-OAP bound Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and ß-TRCP, and accumulation of their substrates Cyclin B1, P27 and E-Cadherin. 6-OAP induced prometaphase arrest and exerted potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and Skp1 inhibitor inactivates crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.

Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments.

BACKGROUND: The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome-editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult. METHODS: In this study, we developed a tumor engraftment index (TEI) to quantify the immunodeficiency response to hematologic malignant cells and solid tumor cells of six immunodeficient mouse strains and C57BL/6 wild-type mouse (WT). RESULTS: Mice with a more severely impaired immune system attained a higher TEI score. We then validated that the NOD-scid-IL2Rg-/- (NSI) mice, which had the highest TEI score, were more suitable for xenograft and allograft experiments using multiple functional assays. CONCLUSIONS: The TEI score was effectively able to reflect the immunodeficiency of a mouse strain.

[FTIR investigation on crystal chemistry of CO(2-)3-substituted apatite solid solutions prepared through different methods].

The CO(2-)3-substituted apatite solid solutions were prepared through different methods. The FTIR and XRD measurements were applied to investigate its crystal chemistry properties. The results indicated that the CO(2-)3-substituted sites in the carbonate hydroxyapatite(CHAP) prepared through homogeneous precipitation method are type-B in which [CO3.OH] tetrahedral-coordinations are substituted for [PO4] tetrahedral-coordinations; the ones in the CHAP prepared through solid phase ions exchange method are type-A in which [CO3] triangle-coordinations are substituted for [OH] in column sites; the ones in the carbonate fluorapatite(CFAP) prepared through solid phase reaction method are type-B in which [CO3.F] tetrahedral-coordinations are substituted for [PO4] tetrahedral-coordinations; the ones in the CHAP prepared through sol-gel method are AB mixed-type. The vibrational band psi 3 is splitted into psi 3-1, psi 3-4 and psi 3F. The psi 3F is combined by psi 3-2 (type-A) and psi 3-3 (type-B) in Gaussian function fitting. When Wco(2-)3 < 3.34%, substitution value of type-A increases with the increasing of CO(2-)3 contents. When Wco(2-)3 = 3.34%, substitution value of type-A has maximum. When 3.34% < Wco(2-)3 < 7.52%, substitution value of type-B increases with the increasing of CO(2-)3 contents. When Wco(2-)3 = 7.52%, substitution value of type-B has maximum.

Downregulated expression of PTK6 is correlated with poor survival in esophageal squamous cell carcinoma.

To investigate the clinical prognostic value of protein tyrosine kinase 6 (PTK6) in patients with esophageal squamous cell carcinoma (ESCC), quantitative RT-PCR and Western blotting were utilized to measure the mRNA and protein expression levels of PTK6 in 29 and eight pairs of ESCC and peritumoral normal esophageal tissues, respectively. Furthermore, the expression of PTK6 protein in 210 ESCCs was examined with immunohistochemistry (IHC), and its clinical value was analyzed using Kaplan-Meier plots and the Cox proportional hazards regression model. The results found that the expression levels of both PTK6 mRNA and protein in ESCC tissues were significantly lower than those in peritumoral normal esophageal tissues. Regarding the IHC analysis of ESCC, the cytoplasmic expression of PTK6 was significantly correlated with tumor grade (P < 0.001). Compared with patients with low PTK6 expression, ESCC patients with overexpression of PTK6 displayed preferable disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P = 0.001, respectively), especially in stage II disease (P = 0.002 and P = 0.021, respectively). PTK6 was evaluated as an independent prognostic factor for ESCC using multivariate Cox regression analysis. All data demonstrated that the expression level of PTK6 is an independent prognostic factor in ESCCs. Low expression of PTK6 is correlated with poor DFS and OS in ESCCs.

Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study.

Transarterial chemoembolization (TACE) has therapeutic effects in patients with unresectable hepatocellular carcinoma (HCC), but its impact on the cellular immune response during disease progression is largely unknown. Here we conducted a prospective study to evaluate the effect of TACE on immune status and to identify prognostic immune markers governing treatment success. In this study, 51 stage III HCC patients, 28 stage I HCC patients (TNM classification) and 20 healthy donors were enrolled. Flow cytometry and cytometric bead array were used to evaluate the circulating immune cell subsets, including CD4(+) T cells (Th1, Th17 and Treg cells), CD8(+) T cells, NK cells, and NKT cells, and plasma cytokines before TACE and 30 days after TACE. Interestingly, among those immune parameters, the frequency of circulating Th17 cells was higher in stage III HCC patients than in stage I HCC patients (P = 0.015) and healthy donors (P<0.001). Moreover, an increased frequency of circulating Th17 cells was observed 30 days after TACE (Th17 D30 ) compared with the baseline level (P = 0.036). Kaplan-Meier analysis demonstrated that Th17 D30 was positively associated with overall survival (OS; P = 0.007) and time to progression (TTP; P = 0.009). Multivariate Cox analysis revealed that Th17 D30 was an independent prognostic factor for OS (HR = 0.317, P = 0.032) and TTP (HR = 0.304, P = 0.010). These results provide a potential prognostic marker for stage III HCC patients undergoing TACE and may be useful for identifying patients who can benefit from adjuvant immunotherapies.

[Expression of galectin-3 in liver metastasis of colon cancer and the inhibitory effect of modified citrus pectin].

OBJECTIVE: To observe the expression of galectin-3 in the liver metastasis of colon cancer in mice and the inhibitory effect of modified citrus pectin (MCP) on galectin-3 expression. METHODS: Seventy-five Balb/c mice were randomized into 5 groups, namely the negative control, positive control, low-concentration MCP, moderate-concentration MCP and high-concentration MCP groups. CT26 colon cancer cells were injected into the subcapsule of the mouse spleen to establish liver metastasis models of colon cancer, but the mice in the negative control group received no tumor cell injection. MCP was added into the drinking water of the mice at the concentrations of 0, 1.0%, 2.5% and 5.0% (m/V). The liver metastasis was observed 3 weeks after tumor cell inoculation. Enzyme-linked immunosorbent assay was performed to determine the serum galectin-3 level. A tissue microarray of the liver metastasis was prepared for immunohistochemical detection of galectin-3 expression in the liver metastasis. RESULTS: In the positive control, low-, moderate- and high-concentration MCP groups, the rates of liver metastasis were 100%, 80%, 73.3% and 60%, respectively. The number of liver metastases in high-concentration MCP group was significantly smaller than that in the positive control group (P<0.05). In the 4 groups with tumor cell inoculation, the median volume of the primary lesions in the spleen was 1.51, 0.93, 0.77 and 0.70 cm(3), respectively, which were significantly smaller in the moderate- and high-concentration MCP groups than in the positive control group (P<0.05). The serum galectin-3 level in the positive control group and MCP-treated groups were significantly higher than that in the negative control group (P<0.01), but similar between the positive control group and the MCP-treated groups (P>0.05). In the positive control and the MCP-treated groups, the expression of galectin-3 in the liver metastases showed no significant differences (P>0.05). CONCLUSION: The expression of galetin-3 is significantly increased in the liver metastasis of colon cancer, and MCP can effectively inhibit the liver metastasis.