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Aims Alterations in histone proteins can lead to breast tumorigenesis. Selective histone deacetylase 8 (HDAC8) inhibitors with fewer adverse effects have been developed. A more comprehensive study of alterations and its mechanisms in HDAC8 is required. In this study, we investigated mechanisms of dysregulation of HDAC8 expression and its biological role and pathways in breast cancer. Main methods Alterations in HDAC8 were analyzed in Taiwanese breast cancer patients; and in tissue samples from The Cancer Genome Atlas (TCGA) data set that were derived from Western countries. Knockdown by si-HDAC8, treatment with the HDAC8-specific inhibitor PCI-34051, SRB assays, wound healing, Transwell migration assays, Illumina BeadArray™ arrays and Ingenuity Pathway Analysis (IPA) were performed in breast cancer cells. Key findings HDAC8 mRNA expression was upregulated in paired breast cancer tissue from Taiwanese patients and in paired breast cancer tissues from the TCGA data set. Hypomethylation of promoter regions was significantly correlated with HDAC8 mRNA overexpression in 588 breast cancer patients from the TCGA data set and was associated with poor prognosis in early-stage breast cancer. HDAC8 mRNA overexpression was associated with late stages and tumor progression. Wound healing and Transwell migration assays revealed that knockdown by si-HDAC8 or PCI-34051 treatment significantly inhibited breast cancer cell migration. Knockdown by si-HDAC8, Illumina BeadArray™ arrays and IPA found that ID3 and PTP4A2 pathways were regulated by HDAC8 in cancer cell migration. Significance Hypomethylation of the HDAC8 promoter is correlated with HDAC8 overexpression and breast cancer progression and is a potential prognosis marker and drug target.

Eight carbonaceous fractions from aerosols were resolved using the Interagency Monitoring of Protected Visual Environments (IMPROVE) protocol (Chow et al., 1993). The aerosols were collected at the Mountain Lulin Atmospheric Background Station (Mt. Lulin, 2862 m a.s.l.) in Central Taiwan from April 2003 to April 2012. The monthly and yearly levels of organic carbon (OC) and elemental carbon (EC) varied consistently with PM 2.5 mass concentrations during biomass burning (BB) period. The highest monthly carbonaceous content was observed in March and the highest yearly carbonaceous concentration was observed in 2007. This finding is consistent with the BB activity in Indochina and indicates that carbonaceous content is a major component of BB aerosols. Lee et al. (2011) classified four trajectory groups from the air masses transported to Mt. Lulin during the aerosol collection period. For the air masses transported from the BB area (the BB group) in Indochina, the carbonaceous content was greater than the water-soluble ions in PM 2.5 , and the OC/EC ratio (4.8 ± 1.5) was high. With EC as the indicator of primary emission sources, the air masses of the BB group were found to contain more primary than secondary OC. The Anthropogenic group (from the local and free troposphere below the 700-hPa pressure level over the Asian continent) probably contained more secondary than primary OC or the sources of OC and EC could be quite diverse. The average char-EC/soot-EC (low-temperature EC/high-temperature EC) ratios were 3.9 ± 3.5, 0.4 ± 0.4, 0.9 ± 0.8, and 0.3 ± 0.4 for the trajectory groups BB , SNBB (from BB source areas during the non-BB period), Anthropogenic , and FT (from the oceanic area and the free troposphere above the 700-hPa pressure level over the Asian continent), respectively. The presence of a high char-EC/soot-EC ratio confirmed the correct classification of the BB group, whereas the low ratios from the other groups indicated the strong influence of vehicle exhaust. It is noted that higher OC and EC levels were obtained at Mt. Lulin as compared with those obtained at other high-elevation sites. This difference suggested that the Indochina BB plume exhibited a more serious climatic impact on the background air in East Asia than in other places in Asia and Europe. On the basis of the carbonaceous levels of the SNBB and FT groups, the background OC and EC levels of approximately 3000 m in the West Pacific are around 1.33 μg m −3 and 0.35 μg m −3 , respectively.

Laparoscopic rectal cancer surgery is regarded as more complex because of its technical difficulties in pelvic exposure, dissection, and sphincter preservation. This study therefore aimed to investigate the feasibility of laparoscopic resection for low rectal cancer using intersphincteric resection (ISR) and to assess its short-term oncological outcomes. Further, we intended to analyze the learning curve for laparoscopic surgery and identify the factors influencing the learning curve.Patients with low rectal cancer who received open or laparoscopic ISR were retrospectively chart reviewed. The surgical and oncological outcomes were evaluated. Comparisons of operating time, estimated blood loss, surgical outcomes, and histopathologic status were analyzed. Also, operating time was used as a technical indicator for learning curve analysis.The mean estimated blood loss was 265 mL (range, 100-800 mL) in the open group and 104 mL (range, 30-250 mL) in the laparoscopic group. There was a significant difference between these two groups (P 0.001). Operative experience analysis showed that the mean operating time was 402.1 min (range, 210-570 min) in the first stage and 331.4 min (range, 210-450 min) in the second stage, and on pathologic examination the mean number of lymph nodes harvested was 11.1 (range, 5-21) in the first stage and 18.3 (range, 11-31) in the second stage, with statistical differences between these two stages (P = 0.034 and P = 0.004, respectively). Multifactorial analysis showed that operating time was associated with surgeons' experience (18 or ≥18 cases) (odds ratio = 2.918, 95% CI 1.078-7.902). Protective stoma creation was also associated with surgeons' experience (odds ratio = 3.999, 95% CI 1.153-13.86).Our data show that laparoscopic ISR for low rectal cancer is feasible and safe. Surgeons' experience improved operating time and postoperative complications.

Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten(+/-) mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.

Background/purpose The tobacco-specific mitogen nicotine was reported to correlate with cancer progression and tumorigenesis in breast cancer. Metastasis is a major cause of cancer death, so the influence of nicotine on breast cancer cell migration is also of interest. Our aim is to elucidate the mechanisms of nicotine-enhanced migration of breast cancer cells and thereby achieve better control of metastasis. Methods The influence of nicotine on breast cancer cell migration was evaluated by trans-well and wound-healing migration assays. Receptor-mediated migration was studied with both a small molecule inhibitor and small interfering RNA (siRNA). Results The alpha9 nicotinic acetylcholine receptor, α9nAChR, was identified in breast cancer cell lines MCF-7 and MDA-MB-231. Nicotine enhanced cell migration in both trans-well and wound-healing migration assays. We used a specific inhibitor and siRNA to demonstrate that α9nAChR is the key modulator in mediating nicotine-enhanced breast cancer cell migration through up-regulation of fibronectin and vimentin. Conclusion Nicotine treatment enhanced breast cancer metastasis through α9nAChR signaling via enhanced fibronectin and vimentin expression.

Colorectal cancer is the third most commonly diagnosed malignancy in the world. The risk factors include inherited genetic mutations and environmental elements such as a high-fat diet, low-fiber diet and sedentary lifestyle. Cigarette smoking is a serious worldwide health problem and the leading cause of preventable death. Although smoking increases the risk of cardiovascular disease and various cancers such as lung, oral and some gastrointestinal cancers, smoking is currently not recognized as a risk factor of colorectal cancer by either the International Agency for Research on Cancer (IARC) or the US Surgeon General. Accumulating epidemiological studies indicate that cigarette smoking is positively correlated to colorectal adenomatous polyps, and positive associations between cigarette smoking and colorectal cancer risk have been reported. Long-term cigarette smoking increases the risk of colorectal cancer mortality and the likelihood of a mutation occurring in the adenomatous polyposis coli (APC) tumor suppressor gene, which has a "gatekeeper" function in the colonic mucosa. Heavy smoking is associated with an increased risk of obtaining a mutation in BRAF, but not KRAS. Current and long-term smokers are at elevated risk of microsatellite instability high (MSI-H) colorectal cancers and an estimated one in five MSI-H colorectal cancers is attributable to cigarette smoking. Nicotine and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are two of the most causal elements for smoking-related cancers. Nicotine and NNK have been shown to induce colon cancer growth and even enhance the migration of colon cancer cells, which is a major cause of cancer death. In conclusion, cigarette smoking should be considered a risk factor of colorectal cancer.

Background The intersphincteric resection technique has been used to extend the opportunity for sphincter preservation in patients with very low rectal cancer. The aim of this study is to assess the long-term oncological and functional outcomes of intersphincteric resection. Methods Patients with extraperitoneal rectal cancer were treated and retrospectively chart reviewed. The oncological and functional outcomes were evaluated. Comparisons of the overall disease-free survival and recurrence were analyzed for the different surgical procedures. Results From July 2002 to August 2009, 162 patients with extraperitoneal rectal cancer were retrospectively chart reviewed. One-hundred one patients (62.3%) underwent low anterior resection, 26 patients (16%) received radical proctectomy and intersphincteric resection with coloanal anastomosis, and 23 (14.2%) had abdominoperineal resection. The sphincter preservation rate was 80%. In the intersphincteric resection group, overall survival rates at 3 and 5 y were 83% and 83%, and disease-free survival at 3 and 5 y were 82% and 76%, respectively. The mean stool frequency was 4.7 per 24 h. There were 38.1% of patients suffering from stool fragmentation, and 23.8% had nocturnal defecation. About one-third of the patients required antidiarrheal medications. Overall, 90.8% of patients were satisfied with the functional results of surgery. Conclusions Our data show intersphincteric resection for low rectal cancer is feasible and safe. Preoperative radiotherapy may negatively affect symptom-specific quality of life.

This paper describes the consequences of alanine-scanning mutagenesis on 28 positions of the second epidermal growth factor (EGF-2) domain of factor IX. We identified four positions of Gln97, Phe98, Tyr115, and Leu117 that are critical for secretion of factor IX. Of the remaining mutations, 4 mutants (V86A, E113A, K122A, and S123A) are as active as wild-type factor IX (IXwt); 16 (D85A, K100A, N101A, D104A, N105A, R116A, E119A, T87A, I90A, K91A, R94A, E96A, S102A, K106A, T112A, and N120A) retain reduced but detectable activity, and 4 (N89A, N92A, G93A, and V107A) are nearly inert in the clotting assay. Both factor XIa and the factor VIIa-tissue factor complex effectively catalyzed the activation of these mutants except N89A. The mutant V107A failed to form the factor tenase complex with factor VIIIa because of a 35-fold increase in K d . The mutants N89A and N92A did not compete with factor IXwt for factor VIIIa binding, and G93A exhibited a 6-fold increase in K i values in the competitive binding assay. It appears that mutations at these positions have significantly affected the interaction between factor IX and factor VIIIa, although other mutations had little effect on the binding of factor IX to factor VIIIa. Mutations in two regions, Thr87–Gly93 and Asn101–Val107, significantly increased theK m value of factor IXa (2–10-fold) in cleavage of factor X in the absence of factor VIIIa. In the presence of factor VIIIa, the catalytic efficiency of each mutant toward factor X paralleled its clotting activity. Briefly, we propose two relatively distinctive functions of factor IX for two adjacent regions in the EGF-2 domain; the first loop region (residues 89–94) is involved with the binding of its cofactor, factor VIIIa, and the third loop with connected β-sheets (residues 102–108) is involved in the proper binding to the substrate, factor X.