TMEM16A overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-ß signaling.

TMEM16A is a newly identified calcium activated chloride channel, and has been reported to be overexpressed by various solid malignant cancers to promote proliferation and invasion, yet little is known about its role in gastric cancer(GC). Therefore, we investigated the role of TMEM16A in GC and its clinical significance by a retrospective analysis of 367 GC patients, and in vitro study was performed for validation and underlying molecular mechanism.TMEM16A was significantly upregulated and amplified in GC tissues, and its overexpression was positively correlated with disease stage, negatively with patient survival and identified as an independent prognostic factor for patient outcome. A negative correlation between TMEM16A and E-cadherin was found in 367 GC specimens. TMEM16A silencing significantly decreased calcium activated chloride currents, impaired TGF-ß secretion, reduced E-cadherin expression, and inhibited the migration and invasion without affecting proliferation of GC cells (AGS and BGC-823). Supplement of TGF-ß reverted the effects of TMEM16A silencing on E-cadherin expression, cell migration and invasion.In conclusion, TMEM16A promotes invasion and metastasis in GC, and might be a novel prognostic biomarker and potential therapeutic target in the treatment of GC.

Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of an open-label, single-arm, multicenter trial.

BACKGROUND: The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients (n = 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. RESULTS: The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. CONCLUSION: The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956).

[Therapeutic effect of sorafenib on portal hypertension: research progress and mechanisms].

OBJECTIVE: Portal hypertension, as one of the major complications of liver cirrhosis, is a common clinical syndrome characterized by an increased portal pressure and the formation of portal-systemic collaterals. Currently no ideal therapeutic agent has been available for portal hypertension. Sorafenib is an oral tyrosine kinase inhibitor that has been shown to significantly improve blood flow dynamics, inhibit angiogenesis, reduce liver fibrosis and decrease portal pressure in the treatment of portal hypertension. The authors review the progress in the research of sorafenib in the treatment of portal hypertension and the mechanisms of its actions.

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.

BACKGROUND: Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS: 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Effect of drug-light interval on the mode of action of Photofrin photodynamic therapy in a mouse tumor model.

Our objective was to examine the effect of time intervals between Photofrin injection and laser irradiation [i.e., drug-light interval (DLI)] on the mode of action of Photofrin photodynamic therapy (PDT). Kunming mice transplanted with sarcoma-180 cells were used as an animal model. The tumor-bearing mice in the control group were given neither photosensitizer nor laser irradiation. PDT groups were given intravenous (i.v.) injection of Photofrin (7.5 mg/kg) prior to being irradiated with a 630 nm laser at 120 J/cm(2) at different DLIs (1 min-48 h). Tumors and overlying skin were visually examined daily. Histopathological and electron microscopic examinations were carried out 48 h after PDT. Survival rates were recorded. The mice in the groups that had experienced short DLIs (<60 min) showed stronger skin reactions than the groups subjected to long DLIs (>6 h). Histological examination showed that antitumor effects were achieved mainly by the destruction of tumor blood vessels and the formation of thrombosis at short DLIs, whereas, at long DLIs, the tumor cells were killed directly by PDT-mediated cytotoxicity. Electron microscopy revealed various degrees of mitochondrial swelling. The survival rate of the mice subjected to long DLIs was slightly higher than that of the mice subjected to short DLIs. Both vascular (e.g., tumor vessel destruction) and cellular (e.g., cytotoxicity) effects contributed to Photofrin PDT-induced tumor ablation.

Generation of robust cytotoxic T lymphocytes against prostate specific antigen by transduction of dendritic cells using protein and recombinant adeno-associated virus.

Prostate cancer is the most common male cancer and there is an urgent need for adjuvant therapy such as immunotherapy. Recombinant adeno-associated virus type 2 (rAAV) vectors are useful for antigen gene-loading of human dendritic cells (DC) and for the rapid generation of cytotoxic T lymphocytes (CTL). In this study, we report a protocol for AAV-loading of DC with the AAV-loading of self-antigen prostate specific antigen (PSA) resulting in generation of CTL. PSA and cytokine expression, Cell surface marker analysis of DC and CTL cells were done using a FACScalibur flow cytometer. Chromium-51 release assay was used to analyze the killing activity of CTL. It was found that AAV-loading of DC with the PSA gene is superior to PSA protein loading of the same antigen for generating effective CTL. AAV/PSA-loading of DC was found to result in: (1) strong, rapid PSA-specific, MHC Class I-restricted CTL, (2) PSA expression in DC, (3) high CD80, CD83, and CD86 expression on DC, (4) high level of IL-12 and low level of IL-10 in DC, (5) T cell populations with significant interferon gamma (IFNgamma) expression, but low IL-4 expression, (6) high proliferation of T cell populations, (7) high CD8:CD4 and CD8:CD56 T cell ratios. The reason for generation of robust CTL is partly explained by the characteristics of DC and CTL described. This protocol may be useful for adoptive immunotherapy against self antigens such as PSA for prostate cancer.

[Effects of pirarubicin chemotherapy combined with hyperthermia on gastric cancer in vitro].

OBJECTIVE: To evaluate the effect of pirarubicin (THP) in combination with hyperthermia on gastric cancer tissues in vitro and explore the underlying mechanisms. METHODS: In vitro three-dimensional culture models were established with tissue biopsies from 36 patients with pathologically confirmed gastric cancer. The tumor cell viability was measured by MTS-PMS assay, and HE staining was used to study the histomorphological changes of the tissues following chemotherapy and hyperthermia. RESULTS: Synergistic tumor cell-killing effects of cisplatin, THP, and mitomycin with hyperthermia was observed in the tumor tissues (P=0.000), and THP exhibited stronger cytotoxic effects than the other drugs. Histomorphological study suggested strong killing effects of THP on the tumor tissues, which displayed disrupted tissue structure, cellular degradation and necrosis, karyopyknosis and karyolysis, with cytoplasm loss. The anti-tumor effects of THP were associated with clinical staging and pathological grading of the tumors (P=0.000), but not with the patients' gender, age, tumor size and preoperative CEA levels (P>0.05). CONCLUSION: Pirarubicin shows good synergistic effects with hyperthermia, and the cytotoxicity of pirarubicin against gastric cancer tissue is enhanced considerably by mild hyperthermia. THP can be a potential therapeutic drug for intraperitoneal chemohyperthermia.

[Effect of Scutellaria barbata extract against human hepatocellular Hep-G2 cell proliferation and its mechanism].

OBJECTIVE: To observe the effects of Scutellaria barbata extract (ESB) on human hepatoma cell line Hep-G2 proliferation in vitro and explore the mechanism. METHODS: The inhibitory effect of ESB on Hep-G2 proliferation was estimated by MTT assay, and the morphological changes of the cells were observed under optical and electron microscopes. Distribution of cell cycle, cell apoptosis and the protein expressions of apoptosis-associated genes as bcl-2, bax and fas were analyzed using flow cytometry. RESULTS: ESB inhibited the proliferation of Hep-G2 cells in a time- and dose-dependent manner. ESB treatment for 72 h resulted in changes of early apoptotic morphology of the cells as observed under optical and the transmission electron microscopes and increased cell apoptosis. Cell cycle analysis revealed decreased S-phase and increased G0/G1-phase cells. Fas expression was significantly up-regulated in response to ESB treatment whereas Bcl-2 and Bax expressions underwent no significant changes. CONCLUSION: ESB can inhibit Hep-G2 cell proliferation, induce cell cycle block, and increase cell apoptosis, which may relate to the activation of FNFR superfamily.

[Inhibition activity of Scutellariae barbata extracts against human hepatocellular carcinoma cells].

OBJECTIVE: To investigate the inhibition effect of Scutellariae barbata extracts on the proliferation of human hepatocellular carcinoma cell line QGY-7701. METHODS: The inhibition activity of the extracts against cell line QGY-7701 was estimated by MTT assay. Morphologic changes of the cells were observed under light microscope and electronic microscope. Cell cycle distribution, cell apoptosis and expressions of apoptosis-associated genes as Bcl-2, Bax and Fas were analyzed by flow cytometry. RESULTS: Extracts of Scutellariae barbata could inhibit the proliferation of QGY-7701. When treated with the extracts for 72 h, cells at the early stage of apoptosis showed morphologic changes, apoptotic cells increased, cells at G0/G1 phase decreased and those at G2/M phase increased, the expression of Bax significantly up-regulated and that of Bcl-2 down-regulated with no change in Fas gene. CONCLUSION: The extracts of Scutellariae barbata inhibit the proliferation of QGY-7701, which may relate to the activation of anti-oncogene Bcl-2, induction of cell apoptosis and inhibition of G to S phase cell cycle progress.

[Inhibitory effect of Biejiajianwan pills on tumor growth and proliferating cell nuclear antigen expression in mice bearing H22 cell-induced tumor].

OBJECTIVE: To study the anti-tumor effect of Biejiajianwan pills and explore its mechanism. METHODS: Mice bearing neoplasm induced by H22 cell inoculation were randomized into 4 groups, namely the negative control group, positive control group (with cyclophosphamide treatment), and high- and low-dose Biejiajianwan pill group. The tumor-bearing mice received corresponding treatments for 15 consecutive days, after which their thymuses and spleens were isolated and weighed to calculate the thymus and spleen indices. The tumor mass was also weighed and the tumor inhibition rate calculated. Immunohistochemistry was performed to evaluate the expression intensity of proliferating cell nuclear antigen (PCNA) in the tumor tissue. RESULTS: The pills significantly inhibited the growth of the implanted tumor and reduced the expression of PCNA in the tumor. CONCLUSION: One of the possible mechanisms of the anti-tumor effects of Biejiajian pills might be associated with the inhibition of PCNA expression in the tumor.

[Prognostic analysis of stage III-IV non-small cell lung cancer patients treated by traditional chinese medicine].

BACKGROUND & OBJECTIVE: Chemotherapy is a treatment for stage III-IV non-small cell lung cancer (NSCLC), but the efficacy is not ideal. Traditional Chinese medicine (TCM) has certain effect on NSCLC. This study was to investigate various factors that affect the prognosis of advanced NSCLC, and evaluate the role of TCM in enlonging survival time of patients with stage III-IV NSCLC. METHODS: The NSCLC patients who meet the inclusive criteria were randomized into TCM group, combination (TCM plus NP regimen) group, and chemotherapy group, and received relevant treatments. The median survival time (MST) was calculated by Kaplan-Meier method. The prognosis of the patients was analyzed by COX regression method. RESULTS: A total of 294 stage III-IV NSCLC patients were enrolled, of which 99 were in TCM group, 103 in combination group, 92 in chemotherapy group. The MST were 292 days in TCM group, 355 days in combination group, and 236 days in chemotherapy group; the cumulative survival rates were 45.38%, 48.86%, and 42.17%, respectively (P>0.05). Cox regression analysis indicated that therapy, gender, disease course, erythrocyte sedimentation, KPS score, tumor size, and patient's weight were independent prognostic factors of stage III-IV NSCLC. CONCLUSION: Compare with chemotherapy alone, TCM combined with chemotherapy may prolong the survival time of stage III-IV NSCLC patients.

Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid.

AIM: To ascertain the molecule mechanism of nuclear factor-kappaB (NF-kappaB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS). METHODS: Sixty rats with TNBS-induced colitis were treated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP). Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-kappaB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IkappaB protein in colonic mucosa was detected by using Western Blot analysis. Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction. RESULTS: Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kappaB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IkappaB protein in colonic mucosa were blocked by curcumin treatment. Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed. CONCLUSION: This study shows that NF-kappaB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD). The findings suggest that NF-kappaB inhibitor curcumin could be a potential target for the patients with IBD.

[Prevention and therapy of radiation-induced pulmonary injury with traditional Chinese medicine].

OBJECTIVE: To explore appropriate therapy with traditional Chinese medicine for radiation pulmonary injury. METHODS: On the basis of the features of its pathogenesis and development, clinical manifestations, and laboratory findings, the radiation-induced lung injuries were classified into latent, acute and progressive stages, and different treatment principles were applied accordingly. For the injuries in the latent phase, the treatment was administered to promote the vital energy and nourish Yin, and also to moisten the lung and relieve the coughing. Management of acute injuries included clearing away heat and toxic materials, releasing inhibited lung energy and dissipating phlegm. Treatment of promoting the vital energy and blood circulation, improving inspiration and invigorating the kidney was exercised for injuries in progressive phase. RESULTS: Both the physicians practicing traditional Chinese medicine and Western medicine found it easier to determine the optimal timing for instituting the treatments after the staging of the injuries. It was observed that complementary treatment with traditional Chinese medicine resulted in reduction of the incidence of acute radiation-induced pneumonia, esophagitis, leucopenia, recurrence and metastasis, and the patients had better quality of life with good appetite, sleeping and spirit. CONCLUSIONS: This treatment is easy and practical, and also incorporates the Western medicine to the principles of instituting different treatments in accordance with different diagnoses in traditional Chinese medicine.

[Clinical study of the effects of radiotherapy in combination with traditional Chinese medicine on non-small cell lung cancer].

OBJECTIVE: To study the therapeutic effects of radiotherapy combined with traditional Chinese medicine (TCM) on non-small cell lung cancer (NSCLC). METHODS: Ninety-two patients with NSCLC were randomly divided into combined treatment group (n=50) and radiotherapy group (n=42). The former group was given TCM in combination with radiotherapy, and the latter group received radiotherapy only. The adverse effects and quality-of-life (QOL) of all the patients were observed after the treatments. RESULTS: The incidence of adverse effects was much lower in combined treatment group than in radiotherapy group, and significantly greater improvement in QOL of the patients was observed in the former group (P<0.01). CONCLUSION: TCM in the combined treatment for patients with NSCLC can reduce the adverse effects of radiotherapy, and improve the life quality of the patients.