抗原穴位注射增强机体免疫功能的神经免疫调节作用

目的 探讨神经免疫调节在抗原穴位注射增强机体免疫功能的作用。方法 采用免疫组化、免疫荧光标记和RT－PCR定量分析技术,观察了不同途径免疫的大鼠中枢神经的下丘脑外侧区（LH）和杏仁核区（AA0中IL－1β、IL－6的表达与脾脏单个核细胞的IL－1β、IL－2γ变化的关系。结果 抗原穴位注射组小鼠LH和AA脑区IL－10β、IL－6的表达明显高于皮下注射组。但阳性细胞表达的高峰时间相似。免疫荧光标记结果显示细胞因子阳性细胞为神经元。穴位免疫组脾脏单个核细胞IL－2和IFN－γ的表达明显高于皮下免疫组,IL－1β的表达无差异。结论 结果提示抗原经不同注射途径（皮下、穴位）免疫动物,动物中枢神经系统的神经免疫调节功能活动的作用时程是相似的,仅表现为神经免疫调节的作用强度不同;LH和AA脑区IL－1β、IL-6介导的神经免疫调节功能与机体的免疫功能状态呈正相关;神经元神经免疫调质／递质的来源。抗原经穴位注射增强机体免疫功能的作用机制可能为穴位免疫可更有效的动员中枢神经系统的免疫相关脑区的神经免疫调节功能,参与对免疫系统的功能调节。     

Mid- and post-ABVD gallium scanning predicts for recurrence in early-stage Hodgkin's disease

PURPOSE: To determine the efficacy of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for patients with Hodgkin's disease and to identify predictors of outcome with this regimen. METHODS: Between 1987 and 1998, 175 patients with Stage I-IV Hodgkin's disease received ABVD as part of initial treatment. Overall survival (OS), freedom-from-treatment-failure (FFTF), and progression-free survival (PFS) were calculated using the Kaplan-Meier technique. Log-rank tests were used to identify univariate predictors of OS, FFTF, and PFS. Specifically, restaging gallium scan results and clinical response after chemotherapy were separately evaluated. RESULTS: The median follow-up time was 64 months. The 5-year OS, FFTF, and PFS rates were 90%, 85%, and 82%, respectively. For Stage I-II patients, restaging gallium scan results and clinical response after chemotherapy were highly predictive of OS, FFTF, and PFS (p < 0.0001). Other significant predictors for higher OS included age <50 (p = 0.002), female gender (p = 0.047), and absence of B symptoms (p = 0.043). Of the 20 patients with a positive restaging gallium scan, 4 received high-dose therapy and 16 continued with conventional-dose therapy or received no further treatment. Of these 16 patients, 11 (69%) were disease-free at last follow-up. CONCLUSIONS: Although a positive mid- or postchemotherapy gallium scan was an adverse prognostic factor for OS, FFTF, and PFS, continued treatment with conventional-dose therapy may be adequate in selected patients with positive scans.     

Cancers of the lung,head and neck on the rise：perspectives on the genotoxicity of air pollution

Outdoor air pollution has been recently classified as a class I human carcinogen by the World Health Organization （WHO）. Cumulative evidence from across the globe shows that polluted air is associated with increased risk of lung, head and neck, and nasopharyngeal cancers--all of which affect the upper aerodigestive tract. Importantly, these cancers have been previously linked to smoking. In this article, we review epidemiologic and experimental evidence of the genotoxic and mutagenic effects of air pollution on DNA, purportedly a key mechanism for cancer development. The alarming increase in cancers of the upper aerodigestive tract in Asia suggests a need to focus government efforts and research on reducing air pollution, promoting clean energy, and investigating the carcinogenic effects of air pollution on humans.     

Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity

Several agents targeting the epidermal growth factor receptor (EGFR) have been FDA-approved to treat cancer patients with varying tumor types including metastatic colorectal cancer. Many patients treated with anti-EGFR therapy however do not respond and those that do initially respond often acquire resistance. Here we show a clear correlation between the efficacy of anti-EGFR inhibitors with their ability to inhibit STAT3 activity in A431 epidermoid carcinoma cells and in a series of wt K-RAS expressing human colon cancer cell lines. Furthermore, the ability of cetuximab to inhibit growth also correlated with its ability to inhibit STAT3 activity in tumor xenograft animal studies. In addition, stable knockdown of the STAT3 phosphatase, protein tyrosine phosphatase receptor delta (PTPRD) resulted in enhanced STAT3 activity and subsequent resistance to cetuximab in DIFI colon carcinoma cells. This resistance could be reversed by STAT3 inhibition. Finally, HN5 cells with acquired resistance to the EGFR tyrosine kinase inhibitor, AG1478 displayed greater STAT3 activity than the HN5 control cell line. These AG1478-refractory HN5 cells were re-sensitized to AG1478, cetuximab and erlotinib when co-treated with a STAT3 inhibitor. Taken together, our current data indicates a key role of STAT3 activity in promoting resistance to anti-EGFR therapy and suggests that anti-EGFR therapy in combination with inhibitors that block STAT3 may provide therapeutic benefit for patients with mCRC and other EGFR driven tumor types.     

MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer

Background:

MicroRNAs (miRNAs) are 19-25-nucleotides regulatory non-protein-coding RNA molecules that regulate the expressions of a wide variety of genes, including some involved in cancer development. In this study, we investigated the possible role of miR-143 in colorectal cancer (CRC).

Methods:

Expression levels of human mature miRNAs were examined using real-time PCR-based expression arrays on paired colorectal carcinomas and adjacent non-cancerous colonic tissues. The downregulation of miR-143 was further evaluated in colon cancer cell lines and in paired CRC and adjacent non-cancerous colonic tissues by qRT–PCR. Potential targets of miR-143 were defined. The functional effect of miR-143 and its targets was investigated in human colon cancer cell lines to confirm miRNA–target association.

Results:

Both real-time PCR-based expression arrays and qRT–PCR showed that miR-143 was frequently downregulated in 87.5% (35 of 40) of colorectal carcinoma tissues compared with their adjacent non-cancerous colonic tissues. Using in silico predictions, DNA methyltranferase 3A (DNMT3A) was defined as a potential target of miR-143. Restoration of the miR-143 expression in colon cell lines decreased tumour cell growth and soft-agar colony formation, and downregulated the DNMT3A expression in both mRNA and protein levels. DNMT3A was shown to be a direct target of miR-143 by luciferase reporter assay. Furthermore, the miR-143 expression was observed to be inversely correlated with DNMT3A mRNA and protein expression in CRC tissues.

Conclusion:

Our findings suggest that miR-143 regulates DNMT3A in CRC. These findings elucidated a tumour-suppressive role of miR-143 in the epigenetic aberration of CRC, providing a potential development of miRNA-based targeted approaches for CRC therapy.     

Polyporenic acid C induces caspase-8-mediated apoptosis in human lung cancer A549 cells

Lung cancer continues to be the leading cause of cancer-related mortality worldwide. This warrants the search for new and effective agents against lung cancer. We and others have recently shown that lanostane-type triterpenoids isolated from the fungal species Poria cocos (P. cocos) can inhibit cancer growth. However, the mechanisms responsible for the anticancer effects of these triterpenoids remain unclear. In this study, we investigated the effect of polyporenic acid C (PPAC), a lanostane-type triterpenoid from P. cocos, on the growth of A549 nonsmall cell lung cancer cells (NSCLC). The results demonstrate that PPAC significantly reduced cell proliferation via induction of apoptosis as evidenced by sub-G1 analysis, annexin V-FITC staining, and increase in cleavage of procaspase-8, -3, and poly(ADP-ribose)-polymerase (PARP). However, unlike our previously reported lanostane-type triterpenoid, pachymic acid, treatment of cells with PPAC was not accompanied by disruption of mitochondrial membrane potential and increase in cleavage of procaspase-9. Further, PPC-induced apoptosis was inhibited by caspase-8 and pan caspase inhibitors but not by a caspase-9 inhibitor. Taken together, the results suggest that PPAC induces apoptosis through the death receptor-mediated apoptotic pathway where the activation of caspase-8 leads to the direct cleavage of execution caspases without the involvement of the mitochondria. Furthermore, suppressed PI3-kinase/Akt signal pathway and enhanced p53 activation after PPAC treatment suggests this to be an additional mechanism for apoptosis induction. Together, these results encourage further studies of PPAC as a promising candidate for lung cancer therapy.     

Prediction for distant failure in patients with stage M0 nasopharyngeal carcinoma: the role of standardized uptake value

Distant failure is an important cause of death in stage M0 primary nasopharyngeal carcinoma (NPC). However, a reliable prognosticator for occurrence of distant failure was lacking. Thus, we conducted this study to investigate prospectively the role of standardized uptake value on 18F-FDG for predicting distant failure in stage M0 NPC. Patients with stage M0 primary NPC diagnosed by both conventional work-up (CWU) and 18F-FDG PET were enrolled. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards models were used to identify independent prognosticators. Between January 2002 and July 2003, 65 NPC patients were investigated. Up to the date of analysis, 12 patients died and 13 patients experienced recurrences, among whom 9 had distant failures. The 5-year overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS) were 81.2%, 79.2%, 84.4%, respectively. In multivariate analysis, the following risk factors for poor prognosis were identified: T3-4 (p=0.033) for RFS; and maximal standardized uptake value (SUVmax) of the primary tumor > 12.0 (p=0.012), stage IVa-b (p=0.037), and N2-3 disease (p=0.04) for DRFS. The 5-year DRFS in stage IVa-b patients with SUVmax > 12.0 was significantly lower than that in stage I-III patients with SUVmax < or = 12 (p=0.0001). None of the patients in the latter group developed distant failure. In conclusion, a SUVmax > 12.0 of the primary tumor represents a "metabolic phenotype" for occurrence of distant failure in stage M0 NPC patients. And the combined information of SUVmax and tumor staging can guide the use of neoadjuvant/adjuvant therapy and surveillance protocols to improve distant control.     

A randomised trial of amoxycillin versus clarithromycin in combination with omeprazole for eradication of Helicobacter pylori infection in Singapore

Dual therapy has been reported to produce H.pylori eradication rate of 75-80%. This study is designed to determine the efficacy of omeprazole 20 mg bd in combination with amoxycillin 500 mg tid (Group A), amoxycillin 750 mg tds (Group B) and clarithromycin 500 mg tid (Group C) in Singapore. One hundred and forty-eight patients with H. pylori positive duodenal ulcers between ages of 22 and 69 were enrolled from two centres. There were 48 patients in Group A, 50 patients in Group B and 50 patients in Group C. The medication was given for 14 days. The patients were re-evaluated with an upper GI endoscope 4 weeks after cessation of treatment Successful eradication was defined as H.pylori negative on histology and culture. Based on intention to treat analysis, the eradication rate was 47.8% in Group A, 68% in Group B and 66% in Group C. The difference between GroupA and B were statistically significant (p = 0.04). Based on all patient treated analysis, the eradication rate was 57.5% in Group A, 70.7% in Group B and 75% in Group C. The difference in eradication rates was not statistically significant. Adverse events were reported in 21% of all patients with no difference in the adverse event rate between all groups. The eradication rate achieved with dual therapy in this study was similar to that attained in Western population. Higher dose amoxycillin regime gives a significantly higher eradication than a lower dose amoxycillin.     

Primary leiomyoma of the liver

This case report describes a primary hepatic leiomyoma presenting as a mass lesion detected on ultrasonography of the abdomen in an asymptomatic hepatitis B carrier on routine surveillance. Primary leiomyomata of the liver are rare occurrences, with only 9 cases reported in the literature. The presenting features of primary hepatic leiomyomata and diagnostic approach towards such lesions are discussed. The significance of such tumours in the immunocompromised is also mentioned.     

Promoter methylation of the Wnt/β‐catenin signaling antagonist Dkk‐3 is associated with poor survival in gastric cancer

BACKGROUND:

Abnormal activation of the Wnt/β‐catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk‐3 in these cancers and its prognostic significance in gastric cancer.

METHODS:

Dkk‐3 methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony‐formation assay. For survival analyses, the authors used Kaplan‐Meier plots, the log‐rank test, and Cox proportional regression.

RESULTS:

Dkk‐3 was silenced or down‐regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of Dkk‐3 suppressed colony formation. Moreover, methylation of Dkk‐3 was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of Dkk‐3 methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that Dkk‐3 methylation was associated significantly and independently with poor disease survival (relative risk, 2.534; 95% confidence interval, 1.54–4.17; P = .002) in gastric cancer, but not in colorectal cancer. Kaplan‐Meier survival curves revealed that patients who had Dkk‐3 methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have Dkk‐3 methylation (median, 2.68 years; P < .0001; log‐rank test).

CONCLUSIONS:

Epigenetic silencing of the Dkk‐3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients. Cancer 2009. © 2008 American Cancer Society.