BACKGROUND AND AIM: The association between cigarette smoking and survival in patients with colorectal cancer (CRC) is inconsistent. Thus, we aim to investigate whether cigarette smoking is associated with the overall survival rates of CRC patients using a nationwide population-based cohort study in Taiwan. METHODS: Taiwan Cancer Registry and Taiwan's national health insurance research database were used to identify CRC patients from 2011 to 2017. All patients were censored to date of death or the end of 2017. Tobacco use was evaluated by smoking status, duration, and amount of cigarette smoking before cancer diagnosis. Survival was estimated using Kaplan-Meier analysis and Cox regression was used to investigate the effect of smoking on overall survival (OS). RESULTS:A total of 49,837 CRC patients were included for analysis. The Kaplan–Meier survival analysis illustrated smoking to be significant association with OS in CRC patients (log-rank p=0.0123). The multivariable Cox model showed that CRC patients with ever smoking habit had 1.11-fold mortality risk (HR=1.11, 95% CI=1.05-1.16; p.0001) compared with CRC patients whom never smoking. This increased risk was also present in CRC patients who smoking cigarettes 20 per day (HR=1.13; 95% CI=1.02-1.25; p=0.0149) or smoking year of 11-30 years (HR=1.15; 95% CI=1.06-1.24; p=0.0004). Furthermore, stratified analysis of sex and tumour location showed the impact of smoking was higher in male CRC patients or cancer developed in rectum. CONCLUSIONS:Our results indicate that cigarette smoking significantly associates with worse survival in CRC patients. An integrated smoking cessation campaign is warranted to prevent the CRC mortality. KEYWORDS: Colorectal cancer, Cigarette smoking, Survival
Thrombomodulin (TM) is highly expressed in endothelial cells and plays the key role in maintaining physical homeostasis. In addition, many pieces of evidence also show that TM contains the diagnostic value for malignant diseases. TM has been found to correlate with metastatic status in multiple cancers, but its role in prostate cancer progression remains unclear. TM expression was determined in prostate cancer cells (DU-145 and PC-3 cells) using real-time PCR and Western blotting. TM expression was manipulated in prostate cancer cells using TM-specific shRNA and an overexpression system. The proliferation, adhesion, and migratory ability of prostate cancer cells expressing various TM levels were determined using the x'Celligence biosensor system and a transwell migration assay. Higher levels of TM transcription and translation were found in DU-145 cells and were negatively correlated with the low migratory ability of DU-145 cells. After silencing TM expression in DU-145 cells, cell growth decreased, but cell adhesion and migration dramatically increased. TM overexpression in PC-3 cells reduced their metastatic ability. We investigated the possible mechanisms of this phenomenon and determined that the enhanced cell migration was mediated through the expression of E-cadherin and vimentin. TM may be a modulator of hormone-independent prostate cancer (HIPC) metastasis. The downregulation of TM expression enhanced the migratory ability of these cells via an increase in vimentin expression and a decrease in E-cadherin expression.
MicroRNAs (miRNAs) play an essential role in regulating gene expression in normal and malignant cells. Expression of the microRNA-200 (miR-200) family has been correlated with malignancy in cancers. However, whether miR-200a/b plays a role in curcumin-mediated treatment of hepatocellular carcinoma (HCC) is unknown. We performed miRNA array analyses in two different HCC cell lines (HepG2 and HepJ5). The expression patterns of miR-200 family members were assessed with real-time PCR. We overexpressed miR-200 family members using a lentiviral system and selected stably transduced clones with antibiotics. The anticancer effects of curcumin on J5-200a, J5-200b, and J5-control cells were assessed by MTT assay, flow cytometry cell cycle analysis, and TUNEL assay. We found that HepG2 cells, which were more resistant to curcumin treatment than HepJ5 cells, expressed higher levels of miR-200a/b. The MTT assay revealed that the overexpression of miR-200a/b in HepJ5 cells conferred enhanced resistance to curcumin treatment compared with the control cells. By cell cycle analysis and TUNEL assay, we found that apoptosis was increased dramatically in J5-control cells compared with J5-200a and J5-200b cells after curcumin treatment. Finally, we evaluated the levels of Bcl-2, Bax, and Bad, and found a decrease of Bcl-2 levels and increase of Bad levels in the J5-control cells treated with curcumin. The expression levels of miR-200a/b might determine the therapeutic efficacy of curcumin on HCC cells.
Next-generation sequencing provides useful information about gene mutations, gene expression, epigenetic modification, microRNA expression, and copy number variations. More and more computing tools have been developed to analyze this large quantity of information. However, to test and find suitable analytical tools and integrate their results is tedious and challenging for users with little bioinformatics training. In the present study, we assembled the computing tools into a convenient toolkit to simplify the analysis and integration of data between bioinformatics tools.The toolkit, GeneGazer, comprises of two parts: the first, named Gaze_Profiler, was designed for personalized molecular profiling from next-generation sequencing data of paired samples; the other, named Gaze_BioSigner, was designed for the discovery of disease-associated biosignatures from expressional and mutational profiles of a cohort study.To demonstrate the capabilities of Gaze_Profiler, we analyzed a pair (colon cancer and adjacent normal tissues) of RNA-sequencing data from one patient downloaded from the Sequencing Read Archive database and used them to profile somatic mutations and digital gene expression. In this case, alterations in the RAS/RAF/MEK/ERK signaling pathway (activated by KRAS G13D mutation) and canonical WNT signaling pathway (activated by truncated APC) were identified; no EGFR mutation or overexpression was found. These data suggested a limited efficacy of cetuximab in the patient. To demonstrate the ability of Gazer_BioSigner, we analyzed gene-expression data from 192 cancer tissues downloaded from The Cancer Genome Atlas and found that the activation of cAMP/PKA signaling, OCT-3/4 and SRF were associated with colon cancer progression and could be potential therapeutic targets.GeneGazer is a reliable and robust toolkit for the analysis of data from high-throughput platforms and has potential for clinical application and biomedical research.
Bevacizumab is a monoclonal antibody that prevents angiogenesis by inhibiting vascular endothelial growth factor (VEGF) activity. Clinically, it has been used to treat a diverse range of cancer types. In this pilot phase II study, we investigated the efficacy and safety profiles of bevacizumab in combination with docetaxel plus cisplatin for patients with advanced HER2-negative metastatic breast cancer.Between 2005 and 2008, 20 patients with advanced breast cancer were recruited from the Taipei Medical University Hospital. Bevacizumab was administered every two weeks in a 12-cycle treatment with docetaxel plus cisplatin. The primary end-point for this study was the overall response rate. The secondary end-points were progression-free survival and the safety profiles of the combined therapy.The average number of treatment cycles was 10.5 with a response rate of 80%. Neutropenia and neuropathy were the most commonly observed adverse events. Seven patients achieved complete remission and nine patients achieved partial remission. For the overall patient group in this study, the median time-to-progression and overall survival were 28.0 weeks and 52 weeks, respectively. The median time-to-progression and overall survival for the 10 patients that completed all 12 cycles of treatment were 64.0 weeks and 80 weeks, respectively. In one patient, a very rapid reduction in the level of breast cancer lung metastases was observed one week post-treatment.Based on this pilot study, bevacizumab in combination with docetaxel and cisplatin is likely to be an effective treatment option for metastatic breast cancer that warrants further study.
To evaluate the feasibility and safety of the minilaparoscopic cholecystectomy (MLC) and to compare the clinical benefits experienced by patients who undergo MLC with those who undergo laparoscopic cholecystectomy (LC) or 5-mm laparoscopic cholecystectomy (5-mm LC).Prospective consecutive study.A tertiary referral center.From September 1, 2000, through June 30, 2001, 90 patients with symptomatic gallstones were randomized to undergo 1 of these 3 procedures.Minilaparoscopic cholecystectomy, LC, and 5-mm LC.Duration of surgery, loss of blood, length of hospital stay, resumption of solid food intake, quantity of analgesic dosage administered, development of complications, degree of pain at ports 24 and 48 hours after surgery, and overall cosmetic result.Subsequent to excluding 6 patients who were converted to LC, there were 30 patients in the LC group, 29 patients in the 5-mm LC group, and 25 patients in the MLC group. The MLC necessitated a longer time to complete the procedure than was the case for the other 2 procedures. There was no notable difference in the mean dosage of the meperidine hydrochloride (Pethidine) administered between the LC and MLC groups, but an apparent increase in the analgesia requirements for the 5-mm LC group was noted when compared with those of the other 2 groups. There was no remarkable difference in terms of blood loss, resumption of solid food intake, hospital stay subsequent to surgery, or surgical-related complication between these 3 groups. The MLC group did have a lower pain score in the subxyphoid port only at 24 hours after surgery compared with the other 2 groups. The cosmetic results were evaluated and no notable difference was noted at 1 week, 1 month, and 6 months after surgery.Although this study has demonstrated the feasibility and safety of the MLC, it does require a longer surgical time and reflects a reasonably high possibility for the conversion to LC. Furthermore, the MLC did not provide any notable clinical benefit for the tested patients compared with those patients in the LC group. We concluded that there is no reason for the MLC to become the universally accepted mode of treatment for symptomatic gallstones before further improvements are made in the technique and instrumentation.
Autophagy is a survival mechanism that is activated in response to nutrient deprivation. The link between aberrant autophagy and cancer has been increasingly recognized. Survivin, an anti-apoptotic molecule, and the autophagy pathway are correlated with therapeutic responses to cancer. However, the role of autophagy in cancer progression remains unclear. Here, we generated survivin knockdown cells (survivin-KD) by introducing a short interfering RNA (siRNA) into hepatocellular carcinoma (HCC) cells, and we observed a 20 % reduction in the survival of these survivin-KD cells, as determined by MTT assay. In addition, an increased number of stress granules, increased positive staining by acridine orange and a shift in the high side scatter (SSC) cell population in flow cytometry analysis were observed in survivin-KD cells. Furthermore, electron microscopy revealed an increased number of autophagosomes in survivin-KD cells compared with scrambled control cells. Finally, we treated cells with an autophagy inhibitor, 3-MA, and observed a decrease in cell survival in survivin-KD cells compared with scrambled control cells. Our study suggests that an autophagy signal may be activated after the anti-apoptotic molecule survivin is suppressed. This finding implies that autophagy may be an alternative survival pathway in HCC cells and may provide a basis for the development of new therapeutic strategies for HCC.
Abstract Polymerization and de-polymerization of microtubule are responsible for separation of chromosomes during cell division which has been considered to be one of major targets in cancer chemotherapy. In order to develop a newer generation of chemotherapeutic agents with higher efficacy and lower toxicity, a novel microtubule-binding agent (AD1), an analog of thiocolchicine, has been successfully synthesized. We here demonstrated AD1 could effectively kill a panel of seven human hepatocellular carcinoma (HCC) cell lines with varying degrees of differentiation. The IC50 values for all these HCC cell lines, using NCI standard protocol (sulforhodamine B, SRB), ranged from 2 to 50 nM. Cell cycle analysis study by flowcytometer unveiled that AD1 could evoke a dose-dependent cell cycle arrest in the G2/M phase. Further immunoflurorescence studies revealed that AD1 could also disrupt tubulin polymerization which would be responsible for the G2/M arrest. These prominent events provoked the disruption of cellular microtubule networks and prevented the proper formation of spindle apparatus and consequently resulted in the mitotic cell death. Interestingly, we also observed that AD1 could induce transcription factor ATF6 cleavage and subsequent reduction of the level of ER stress chaperone protein Grp78, and phosphorylated Akt expression. In vivo toxicity studies demonstrated that AD1, with maximum tolerance dose (MTD) of 150 mg/kg, was remarkably less toxic to normal C3H/HeN mice than colchicine (MTD of 1.6 mg/kg). The in vivo efficacy study of AD1 on HCC xenografts are now being investigated in nude mouse model in our laboratories. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4424.
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