[Show abstract][Hide abstract] ABSTRACT: To compare the dosimetric effects of Acuros XB (AXB) and Anisotropic Analytical Algorithm (AAA) on volumetric modulated arc therapy (VMAT) planning for postoperative prostate cancer patients irradiated using an endorectal balloon (ERB).
We measured central axis doses with film in a phantom containing an air cavity, and compared measurements with calculations of the AAA and AXB. For clinical study, 10 patients who had undergone whole pelvic radiotherapy (WPRT) followed by prostatic bed-only radiotherapy (PBRT) using VMAT were enrolled. An ERB was used for PBRT but not for WPRT. To compare dosimetric parameters, the cumulative dose-volume histograms, mean, maximum, and minimum doses were measured for the planning target volume. Homogeneity of plans were confirmed using V95%, V107% (VX%, percentage volumes receiving at least X% of prescribed doses) and conformity indices (homogeneity index [HI], conformity index [CI], and conformation number [CN]). We compared volumes of the organ-at-risk receiving 10% to 100% (10-tier at 10% interval) of prescribed doses (V10% - V100%).
In the phantom study, the AAA showed larger disagreement with the measurements, and overestimated the dose in the air cavity, comparing with the AXB. For WPRT planning, the AAA predicted a lower maximum dose and V107% than the AXB. For PBRT planning, the AAA estimated a higher minimum dose, lower maximum dose, and smaller V107%, and larger V95% than the AXB. Regarding the conformity indices, the AAA was estimated to be more homogenous than the AXB for PBRT planning (HI, 0.088 vs. 0.120, p = 0.005; CI, 1.052 vs. 1.038, p = 0.022; and CN, 0.920 vs. 0.900, p = 0.007) but not for WPRT planning. Among V10% to V100% of the rectum, the PBRT exhibited significant discrepancies in V30%, V40%, V70%, V80%, and V90%; while the WPRT did in V20% and V30%.
The phantom study demonstrated that the AXB calculates more accurately in the air cavity than the AAA. In the clinical setting, the AXB exhibited different dosimetric distributions in the VMAT plans for PBRT containing an ERB. The AXB should be considered for prostate cancer patients irradiated with an ERB for better applying of heterogeneous condition.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To evaluate the prognostic impact of the lymph node ratio (LNR) in ypStage III rectal cancer patients who were treated with neoadjuvant chemoradiotherapy (NCRT).
Materials and methods:
We retrospectively reviewed the data of 638 consecutive patients who underwent NCRT followed by total mesorectal excision, and postoperative adjuvant chemotherapy for rectal cancer from 2004 to 2011. Of these, 125 patients were positive for lymph node (LN) metastasis and were analyzed in this study.
The median numbers of examined and metastatic LNs were 17 and 2, respectively, and the median LNR was 0.143 (range, 0.02-1). Median follow-up time was 55 months. In multivariate analyses, LNR was an independent prognostic factor for overall survival (OS) (hazard ratio [HR] 2.17, p = 0.041), disease-free survival (DFS) (HR 2.28, p = 0.005), and distant metastasis-free survival (DMFS) (HR 2.30, p = 0.010). When ypN1 patients were divided into low (low LNR ypN1 group) and high LNR (high LNR ypN1 group) according to a cut-off value of 0.152, the high LNR ypN1 group had poorer OS (p = 0.043) and DFS (p = 0.056) compared with the low LNR ypN1 group. And there were no differences between the high LNR ypN1 group and the ypN2 group in terms of the OS (p = 0.703) and DFS (p = 0.831).
For ypN-positive rectal cancer patients, the LNR was a more effective prognostic marker than the ypN stage, circumferential resection margin, or tumor regression grade after NCRT, and could be used to discern the high-risk group among ypN1 patients.
PLoS ONE 09/2015; 10(9):e0138728. DOI:10.1371/journal.pone.0138728 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of brain metastasis from hepatocellular carcinoma (HCC) is increasing because of the improved survival outcome of HCC patients, but the prognosis of these patients is extremely poor. HCC patients with brain metastasis were investigated to identify their prognostic factors for overall survival. Patients with brain metastasis from HCC who had been treated with whole-brain radiotherapy (WBRT) in five hospitals were enrolled in the study. The medical records of the patients were reviewed, and the clinical factors were analyzed to identify the prognostic factors for overall survival. Of the total of 97 patients who were enrolled in the study, 83 were male and the median age at the brain metastases was 56.6 years. Motor weakness (43.3 %) and headache (41.2 %) were common presenting symptoms. The median AFP level was 4180 ng/ml, and 81 patients were assessed as belonging to Child-Pugh classification A upon the diagnosis of brain metastasis. WBRT alone in 71 patients, surgery or radiosurgery combined with WBRT as the adjuvant setting in 18 patients, and WBRT as salvage treatment in 8 patients were performed. The median overall survival of the patients was 3.5 months. In the multivariate analysis, the ECOG performance status (PS), Child-Pugh classification, AFP, and treatment aim showed significant association with the overall survival of the patients. Based on these factors, a nomogram predicting the prognosis was developed. The concordance index of the nomogram was 0.74, and the prediction was well calibrated. In conclusion, the survival outcome of patients with brain metastasis from HCC can be predicted with the nomogram constructed from the ECOG PS, Child-Pugh classification, AFP, and treatment aim.
Journal of Neuro-Oncology 09/2015; DOI:10.1007/s11060-015-1926-7 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate metabolic and textural parameters from pretreatment [(18)F]FDG PET/CT scans for the prediction of neoadjuvant radiation chemotherapy response and 3-year disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC).
We performed a retrospective review of 74 patients diagnosed with LARC who were initially examined with [(18)F]FDG PET/CT, and who underwent neoadjuvant radiation chemotherapy followed by complete resection. The standardized uptake value (mean, peak, and maximum), metabolic volume (MV), and total lesion glycolysis of rectal cancer lesions were calculated using the isocontour method with various thresholds. Using three-dimensional textural analysis, about 50 textural features were calculated for PET images. Response to neoadjuvant radiation chemotherapy, as assessed by histological tumour regression grading (TRG) after surgery and 3-year DFS, was evaluated using univariate/multivariate binary logistic regression and univariate/multivariate Cox regression analyses.
MVs calculated using the thresholds mean standardized uptake value of the liver + two standard deviations (SDs), and mean standard uptake of the liver + three SDs were significantly associated with TRG. Textural parameters from histogram-based and co-occurrence analysis were significantly associated with TRG. However, multivariate analysis revealed that none of these parameters had any significance. On the other hand, MV calculated using various thresholds was significantly associated with 3-year DFS, and MV calculated using a higher threshold tended to be more strongly associated with 3-year DFS. In addition, textural parameters including kurtosis of the absolute gradient (GrKurtosis) were significantly associated with 3-year DFS. Multivariate analysis revealed that GrKurtosis could be a prognostic factor for 3-year DFS.
Metabolic and textural parameters from initial [(18)F]FDG PET/CT scans could be indexes to assess tumour heterogeneity for the prediction of neoadjuvant radiation chemotherapy response and recurrence in LARC.
European Journal of Nuclear Medicine 09/2015; DOI:10.1007/s00259-015-3180-9 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine the anabolic and anticatabolic functions of bavachin in primary rat chondrocytes. With bavachin treatment, chondrocytes survived for 21 d without cell proliferation, and the proteoglycan content and extracellular matrix increased. Short-term monolayer culture of chondrocytes showed that gene induction of both aggrecan and collagen type II, major extracellular matrix components, was significantly upregulated by bavachin. The expression and activities of cartilage-degrading enzymes such as matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs were inhibited significantly by bavachin, while tissue inhibitors of metalloprotease were significantly upregulated. Bavachin inhibits the expression of inducible nitric oxide synthase, a representative catabolic factor, and downregulated the expression of nitric oxide, cyclooxygenase-2, and prostaglandin E2 in a dose-dependent manner in chondrocytes. Our results suggest that the bavachin has anabolic and potent anticatabolic biological effects on chondrocytes, which may have considerable promise in treating articular cartilage degeneration in the future.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to compare the prognostic efficacy of the number and location of positive lymph nodes (LN), LN ratio (LNR), and log odds of positive LNs (LODDs) in high-risk cervical cancer treated with radical surgery and adjuvant treatment.
Fifty high-risk patients who underwent radical hysterectomy and pelvic node dissection followed by adjuvant treatment were analyzed retrospectively. The patients had FIGO stage IA2-IIB. Upper LN is defined as common iliac or higher LN, and LNR is the ratio of positive LNs to harvested LNs. LODDs is log odds between positive LNs and negative LNs. Radiotherapy was delivered to the whole pelvis with median 50.4 Gy/28 Fx ± to the para-aortic regions. Platinum-based chemotherapy was used in most patients (93%). The median follow-up duration was 80 months.
The 5-year disease-free survival (DFS) rate was 76.1%, and the overall survival (OS) rate was 86.4%. Treatment failure occurred in 11 patients, and distant failure (DF) was the dominant pattern (90.9%). In univariate analysis, significantly lower DFS was observed in patients with perineural invasion, ≥2 LN metastases, LNR ≥10%, upper LN metastasis, and ≥-1.05 LODDs. In multivariate analysis, ≥-1.05 LODDs was the only significant factor for DFS (p=0.011). Of patients with LODDs ≥-1.05, 40.9% experienced distant failure. LODDs was the only significant prognostic factor for OS as well (p=0.006).
LODDs ≥-1.05 was the only significant prognostic factor for both DFS and OS. In patients with LODDs ≥-1.05, intensified chemotherapy might be required, considering the high rate of DF.
Cancer Research and Treatment 07/2015; DOI:10.4143/crt.2015.085 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the impact of elective whole pelvic radiotherapy (WPRT) versus prostate bed-only radiotherapy (PBRT) on biochemical relapse-free survival (bRFS) in prostate cancer patients treated with salvage radiotherapy following radical prostatectomy (RP).
In our database, 163 lymph node-negative prostate cancer patients who had undergone salvage radiotherapy (SRT) for biochemical relapse after RP between September 2004 and April 2012 were identified. PBRT was administered to 134 patients (the PBRT group), while the remaining 29 patients (the WPRT group) received WPRT.
Median follow-up was 57 months (range 18-122 months). In the propensity score-matched cohort, the 4-year bRFS of the WPRT group was significantly higher compared to the PBRT group (63.1 vs. 43.4 %, p = 0.034). Subgroup analysis showed that the bRFS of patients who had two or more risk factors (seminal vesicle invasion, Roach score for lymph node invasion ≥ 45 %, and number of harvested lymph nodes ≤ 5) and were treated with WPRT was significantly improved compared to those who received PBRT (hazard ratio, HR 0.33; 95 % confidence interval, CI 0.13-0.83; p = 0.018).
Elective WPRT for SRT may improve bRFS in patients with unfavorable risk factors. These results need to be confirmed by a prospective randomized trial.
Strahlentherapie und Onkologie 07/2015; 191(10). DOI:10.1007/s00066-015-0872-9 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Lumbar facet joint degeneration (FJD) may be an important cause of low back pain (LBP) and sciatica. The goal of this study was to characterize cellular alterations of inflammatory factor expression and neovascularization in human degenerative facet joint capsular (FJC) tissue. These alterations in FJC tissues in pain stimulation were also assessed.
FJs were obtained from consented patients undergoing spinal reconstruction surgery and cadaveric donors with no history of back pain. Histological analyses of the FJs were performed. Cytokine antibody array and quantitative real-time polymerase chain reaction (qPCR) were used to determine the production of inflammatory cytokines, and western blotting analyses (WB) were used to assay for cartilage-degrading enzymes and pain mediators. Ex vivo rat dorsal root ganglion (DRG) co-culture with human FJC tissues was also performed.
Increased neovascularization, inflammatory cell infiltration, and pain-related axonal-promoting factors were observed in degenerative FJCs surgically obtained from symptomatic subjects. Increased VEGF, (NGF/TrkA), and sensory neuronal distribution were also detected in degenerative FJC tissues from subjects with LBP. qPCR and WB results demonstrated highly upregulated inflammatory cytokines, pain mediators, and cartilage-degrading enzymes in degenerative FJCs. Results from ex vivo co-culture of the DRG and FJC tissue demonstrated that degenerative FJCs increased the expression of inflammatory pain molecules in the sensory neurons.
Degenerative FJCs possess greatly increased inflammatory and angiogenic features, suggesting that these factors play an important role in the progression of FJD and serve as a link between joint degeneration and neurological stimulation of afferent pain fibers.
Osteoarthritis and Cartilage 06/2015; DOI:10.1016/j.joca.2015.06.009 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to evaluate objective cosmetic outcomes and factors related to breast-conserving therapy (BCT) using the BCCT.core software.
Fifty-one patients who received BCT with informed consent were evaluated using the BCCT.core software. Patients were divided into two groups based on the BCCT score: excellent or good (n=42) vs. fair or poor (n=9). Analysis of clinical factors was performed to determine factors affecting cosmetic outcomes.
The objective cosmetic outcome of BCT measured using the BCCT.core software was excellent in 10% of patients, good in 72%, and fair in 18%. None of the patients were classified as poor outcome. Tumor characteristics, systemic adjuvant therapy (chemotherapy and hormonal therapy), and radiation dose or energy of electron boost did not show correlation with the score measured by the BCCT.core program (P>0.05). In univariate analysis, maximum dose within the breast (Dmax), width of tangential field, and excised tumor volume were smaller in patients with excellent or good by the BCCT.core compared to those with fair or poor (Dmax, 110.2±1.5% vs. 111.6±1.7%, P=0.019; width of tangential field, 8.0±1.1 cm vs. 8.6±0.7 cm, P=0.034; excised tumor volume, 64.0±35.8 cm3 vs. 95.3±54.4 cm3, P=0.067). In multivariate analysis, only Dmax was a significant factor for breast cosmetic outcome with a risk ratio of 1.697 (95% confidence interval 1.006-2.863, P=0.047).
: Objective measurement of cosmetic outcome of BCT using the BCCT.core software was feasible. The cosmetic outcome of BCT may be affected by the maximum dose within the breast.
Cancer Research and Treatment 06/2015; DOI:10.4143/crt.2015.088 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the effect of chemoradiotherapy with PP2 and temozolomide (TMZ) on malignant glioma cells using clonogenic assays and in vivo brain tumor model.
The effect of PP2 on radiosensitivity of U251 and T98G cells was investigated using clonogenic assays. The expression of E-cadherin, MMP2, EphA2, and VEGF was measured by Western blotting and an accumulation of γH2AX foci 6 h after radiotherapy was measured after PP2 treatment. The effect of PP2 on migration, invasion, and vasculogenic mimicry formation (VMF) of U251 cells was evaluated. In an orthotopical brain tumor model with U251 cells, PP2 was injected intraperitoneally with or without oral TMZ before, during and after whole brain radiotherapy. Bioluminescence images were taken to visualize in vivo tumors and immunohistochemical staining of VEGF, CD31, EphA2, and HIF1a was performed.
PP2 increased radiosensitivity of U251 and T98G cells without decreasing survival of normal human astrocytes. Chemoradiotherapy with PP2 and TMZ resulted in increased accumulation of γH2AX foci. PP2 induced overexpression of E-cadherin and suppression of MMP2, VEGF, and EphA2. PP2 also compromised invasion, migration, and VMF of U251 cells. In brain tumors, chemoradiotherapy with PP2 and TMZ decreased tumor volume best, but not statistically significantly compared with chemoradiotherapy with TMZ. The expression of VEGF and CD31 was suppressed in PP2-treated tumors.
s PP2 enhances radiosensitivity of malignant glioma cells and suppresses invasion and migration of U251 cells. Chemoradiotherapy with PP2 and TMZ resulted in non-significant tumor volume decrease.
Cancer Research and Treatment 06/2015; DOI:10.4143/crt.2014.320 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the impact of postoperative chemoradiotherapy (CRT) versus adjuvant chemotherapy alone on recurrence and survival in patients with stage II and III upper rectal cancer undergoing curative resection.
From our institutional database, 190 patients who underwent primary curative resection between 2003 and 2010 for stage II or III upper rectal cancer were identified. None of the patients received preoperative CRT. Of these, 136 patients received postoperative chemotherapy alone (the CTx group) and 54 patients received postoperative CRT (the CRT group). The CRT group had poorer prognostic features (pT4, pN2, poor differentiation, or involved resection margin) compared with the CTx group. To reduce the impact of treatment selection bias on treatment outcomes, propensity score-matching analysis was used.
The matched cohort consisted of 50 CRT and 50 CTx patients with a median follow-up period of 76 and 63 months, respectively. In the matched cohort, CRT resulted in an improved 5-year local control (98.0% vs. 85.2%, p = 0.024) and overall survival rate (89.9% vs. 69.8%, p = 0.021) compared with CTx. In the subgroup analysis to identify subpopulations of patients that benefit most from receiving CRT, local recurrence did not occur in patients who did not have poor prognostic features regardless of the receipt of CRT. For patients with any poor prognostic features, CRT resulted in an improved 5-year local control compared with CTx (96.4% vs. 70.7%, p = 0.013).
After adjusting for clinicopathologic factors by propensity score-matching, postoperative CRT was associated with improved local control and overall survival in stage II and III upper rectal cancer. Our results suggest that surgery followed by chemotherapy alone is acceptable for patients who did not have poor prognostic features, while additional radiotherapy should be given for patients who have any poor prognostic features.
PLoS ONE 04/2015; 10(4):e0123657. DOI:10.1371/journal.pone.0123657 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report generation and characterization of pain-related behavior in a minimally-invasive facet joint degeneration (FJD) animal model in rats. FJD was produced by a non-open percutaneous puncture-induced injury on the right lumbar FJs at three consecutive levels. Pressure hyperalgesia in the lower back was assessed by measuring the vocalization response to pressure from a force transducer. After hyperalgesia was established, pathological changes in lumbar FJs and alterations of intervertebral foramen size were assessed by histological and imaging analyses. To investigate treatment options for lumber FJ osteoarthritis-induced pain, animals with established hyperalgesia were administered with analgesic drugs, such as morphine, a selective COX-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID) (ketorolac), or pregabalin. Effects were assessed by behavioral pain responses. One week after percutaneous puncture-induced injury of the lumbar FJs, ipsilateral primary pressure hyperalgesia developed and was maintained for at least 12 weeks without foraminal stenosis. Animals showed decreased spontaneous activity, but no secondary hyperalgesia in the hind paws. Histopathological and microfocus X-ray computed tomography analyses demonstrated that the percutaneous puncture injury resulted in osteoarthritis-like structural changes in the FJs cartilage and subchondral bone. Pressure hyperalgesia was completely reversed by morphine. The administration of celecoxib produced moderate pain reduction with no statistical significance while the administration of ketorolac and pregabalin produced no analgesic effect on FJ osteoarthritis-induced back pain. Our animal model of non-open percutanous puncture-induced injury of the lumbar FJs in rats shows similar characteristics of low back pain produced by human facet arthropathy. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To test by immunohistochemical (IHC) staining whether carbonic anhydrase (CA) 9 and 12 have an effect on sentinel lymph node (SLN) metastasis in early breast cancer and to find clinicopathologic factors associated with SLN metastasis.
Between June 2003 and June 2011, medical records of 470 patients diagnosed with breast cancer with pT1-2, pN0-2 and M0 were reviewed. Of these 470, 314 patients who underwent SLN biopsy ± axillary dissection were subjects of this study. Using tissue microarray, IHC staining for CA9 and CA12 was performed. Clinicopathologic factors such as patient age, tumour size, lymphatic invasion, hormone receptor status, and the Ki-67 labelling index were analysed together.
The mean age of all patients was 51.7 years. The mean number of harvested SLN was 3.62, and 212 (67.5%) patients had negative SLN. Lymphatic invasion, the Ki-67 labelling index of primary tumours, and CA9 staining of stromal cells, were independent risk factors for SLN metastasis in the multivariate analysis. In 33 patients (10.5%) without the three risk factors, no patient had SLN metastasis. In 80 patients without lymphatic invasion of primary tumours or CA9 staining of stromal cells, only four patients (5%) had positive SLN.
CA9 staining of stromal cells is an independent risk factor for SLN metastasis as well as lymphatic invasion and a low-Ki-67 labelling index of primary tumours in patients with early breast cancer. IHC staining of primary tumours for CA12 was not associated with SLN metastasis.
Cancer Research and Treatment 03/2015; DOI:10.4143/crt.2014.243 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, we examined the anticancer properties of berberine in KB oral cancer cells with a specific focus on its cellular mechanism. Berberine did not affect the cell viability of the primary human normal oral keratinocytes that were used as a control. However, the viability of KB cells was found to decrease significantly in the presence of berberine in a dose-dependent manner. Furthermore, in KB cells, berberine induced the fragmentation of genomic DNA, changes in cell morphology, and nuclear condensation. In addition, caspase-3 and -7 activation, and an increase in apoptosis were observed. Berberine was also found to upregulate significantly the expression of the death receptor ligand, FasL. In turn, this upregulation triggered the activation of pro-apoptotic factors such as caspase-8, -9 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, pro-apoptotic factors such as Bax, Bad and Apaf-1 were also significantly upregulated by berberine. Anti-apoptotic factors such as Bcl-2 and Bcl-xL were downregulated. Z-VAD-FMK, a cell-permeable pan-caspase inhibitor, suppressed the activation of caspase-3 and PARP. These results clearly indicate that berberine-induced cell death of KB oral cancer cells was mediated by both extrinsic death receptor-dependent and intrinsic mitochondrial-dependent apoptotic signaling pathways. In addition, berberine-induced upregulation of FasL was shown to be mediated by the p38 MAPK signaling pathway. We also found that berberine-induced migration suppression was mediated by downregulation of MMP-2 and MMP-9 through phosphorylation of p38 MAPK. In summary, berberine has the potential to be used as a chemotherapeutic agent, with limited side-effects, for the management of oral cancer.
[Show abstract][Hide abstract] ABSTRACT: The neurotrophin-inducible gene VGF plays an important role in the maintenance of organismal energy balance and in the mediation of hippocampal synaptic activity. The regulatory mechanism of VGF transcription is not fully understood. The neuron-restrictive silencer factor (NRSF) binds with the neuron-restrictive silencer element (NRSE), thereby suppressing the transcription of NRSE-containing genes. In this study, we show that the NRSE sequence of the VGF gene critically regulates the repression of VGF expression in NMB cells. Sequence analysis also establishes the presence of two putative NRSEs (NRSE-1 and NRSE-2) in the promoter region of the VGF gene. In reporter gene experiments, a more than eight-fold increase in the promoter activity was observed when both NRSE-1 and NRSE-2 were deleted. Deletion of NRSE-2 alone did not affect the promoter activity, thus indicating that NRSE-1 could be solely responsible for the repression of VGF gene expression. Mutations in the NRSE-1 sequence increased promoter activity. However, no change in activity was observed when NRSE-1 was coexpressed with dominant-negative NRSF, thereby suggesting that endogenous NRSF interacts with NRSE-1. Binding of NRSF to NRSE in a sequence-specific manner was confirmed with chromatin immunoprecipitation assays, respectively. Furthermore, the overexpressed NRSF in PC12 cells significantly suppressed the VGF gene expression by interacting with the NRSE located in the VGF promoter region. Our results indicate that NRSF plays an important role as a repressor of VGF gene regulation in NMB cells through a mechanism that is dependent on VGF-NRSE.
[Show abstract][Hide abstract] ABSTRACT: We investigated Licochalcone-A (Lico-A)-induced apoptosis and the pathway underlying its activity in a pharyngeal squamous carcinoma FaDu cell line. Lico-A purified from root of Glycyrrhiza inflata had cytotoxic effects, significantly increasing cell death in FaDu cells. Using a cell viability assay, we determined that the IC50 value of Lico-A in FaDu cells was approximately 100 µM. Chromatin condensation was observed in FaDu cells treated with Lico-A for 24 h. Consistent with this finding, the number of apoptotic cells increased in a time-dependent manner when FaDu cells were treated with Lico-A. TRAIL was significantly up-regulated in Lico-A-treated FaDu cells in a dose-dependent manner. Apoptotic factors such as caspases and PARP were subsequently activated in a caspase-dependent manner. In addition, levels of pro-apoptotic factors increased significantly in response to Lico-A treatment, while levels of anti-apoptotic factors decreased. Lico-A-induced TRAIL expression was mediated in part by a MAPK signaling pathway involving ERK1/2 and p38. In xenograft mouse model, Lico-A treatment effectively suppressed the growth of FaDu cell xenografts by activating caspase-3, without affecting the body weight of mice. Taken together, these data suggest that Lico-A has potential chemopreventive effects and should therefore be developed as a chemotherapeutic agent for pharyngeal squamous carcinoma.
Food and Chemical Toxicology 01/2015; 77. DOI:10.1016/j.fct.2014.12.013 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to develop a functional collagen membrane that is treated with poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with dexamethasone (DEX) as a bioactive molecule for guided bone regeneration (GBR). The DEX-loaded PLGA microparticles prepared using water-in-oil standard emulsion method were precoated with positively charged polyethylenimine molecules and later immobilized onto the surface of the collagen membrane; the microparticles were physically immobilized using counter charges of positively charged PLGA microparticles and the negatively charged collagen membrane surface. The release profile of DEX over a 4-week immersion study indicated an initial burst release followed by a sustained release. The performance of this system was investigated using rats with calvarial bone defects. The in vivo evaluation of the defects filled with membrane containing DEX-loaded PLGA microparticles indicated enhanced volume and quality of new bone formation compared with defects that were either unfilled or filled with membrane alone. This innovative platform for bioactive molecule delivery more potently induced osteogenesis, which may be exploited in implantable membranes for stem cell therapy or improved in vivo performance. In conclusion, this newly developed collagen membrane treated with drug-loaded PLGA microparticles might be applicable as a promising bone graft substitute for GBR.
Tissue Engineering Part A 12/2014; 20(23-24):3322-3331. DOI:10.1089/ten.tea.2013.0717 · 4.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Because miR-146a expression in articular chondrocytes is associated with osteoarthritis (OA), we assessed whether miR-146a is linked to cartilage degeneration in the spine. Monolayer cultures of nucleus pulposus (NP) cells from the intervertebral discs (IVD) of bovine tails were transfected with a miR-146a mimic. To provoke inflammatory responses and catabolic extracellular matrix (ECM) degradation, cells were co-treated with interleukin-1 (IL-1). Transfection of miR-146a decreases IL-1 induced mRNA levels of inflammatory genes and catabolic proteases in NP cells based on quantitative real-time reverse transcriptase PCR (qRT-PCR) analysis. Similarly, miR146a suppresses IL-1 induced protein levels of matrix metalloproteinases and aggrecanases as revealed by immunoblotting. Disc segments from wild type (WT) and miR-146a knockout (KO) mice were cultured ex vivo in the presence or absence of IL-1 for 3days. Histological and immuno-histochemical (IHC) analyses of disc organ cultures revealed that IL-1 mediates changes in proteoglycan (PG) content and in-situ levels of catabolic proteins (MMP-13 and ADAMTS-5) in the nucleus pulposus of the disc. However, these IL-1 effects are more pronounced in miR-146a KO discs compared to WT discs. For example, absence of miR-146a increases the percentage of MMP-13 and ADAMTS-5 positive cells after treatment with IL-1. Thus, miR-146a appears to protect against IL-1 induced IVD degeneration and inflammation. Stimulation of endogenous miR-146a expression or exogenous delivery of miRNA-146a are viable therapeutic strategies that may decelerate disc degeneration and regain a normal homeostatic balance in extracellular matrix production and turn-over.