Vertebral Fractures in Type 2 Diabetes Patients: Utility of Trabecular Bone Score and Relationship With Serum Bone Turnover Biomarkers.

BACKGROUND: Patients with type 2 diabetes (T2D) have an increased risk for vertebral fracture (VF). The aim of this study is to determine the utility of trabecular bone score (TBS) in T2D patients with VF and the relationship of TBS with serum bone turnover biomarkers (SBTBs). METHODOLOGY: Postmenopausal T2D female patients were prospectively enrolled. All patients received: (1) dual-energy X-ray absorptiometry exam for bone mineral density (BMD), T-score, and TBS values; (2) lateral lumbar spine radiographs for VF assessment; and (3) SBTBs: bone specific alkaline phosphatase and Beta-C-Terminal telopeptides. BMD, T-score, TBS, and SBTBs were tested for association with VF. RESULTS: The study included 285 T2D patients (mean age = 61.1 years) and 32 patients had VF (11.2%). TBS had the strongest association with VF in T2D patients (area under curve 0.775). The TBS cutoff values for VF are 1.279 in T-score ≥1 and 1.236 in T-score <-1. In patients without VF, all sites of BMD and TBS are significantly associated with SBTBs, but in patients with VF, no associations are found between SBTBs and all sites of BMD and TBS. CONCLUSIONS: TBS can assess bone quality in the spine. The low TBS cutoff values for T2D patients with VF imply T2D does impair bone quality. Thus, TBS should be incorporated in VF risk assessment in T2D patients. In addition, a dissociated relationship between BMD and TBS with SBTBs represents imbalanced bone turnover rate and results in bone fragility and VF.

Low vitamin D level was associated with metabolic syndrome and high leptin level in subjects with nonalcoholic fatty liver disease: a community-based study.

BACKGROUND: This study aimed to evaluate the association between serum vitamin D levels and nonalcoholic fatty liver disease (NAFLD) parameters, such as metabolic syndrome (MS), inflammatory cytokines (tumor necrosis factor, high sensitive C-reactive protein) and adipokines (adiponectin, leptin). METHODS: From August 2013 to August 2016, a community-based study was performed in the north-eastern region of Taiwan. All subjects received a demographic survey, blood testing and abdominal ultrasonography (US). The vitamin D level was evaluated by quartile divide or used the classification of deficiency (< 20 ng/ml), insufficiency (20-30 ng/ml) and sufficiency (> 30 ng/ml). RESULTS: Subjects were divided into NAFLD group and normal control (subjects number = 564 in each group) following abdominal US study and matching age and gender. The mean age was 57.1 years in NAFLD group and 57.5 in control group. Subjects in NAFLD group had a lower mean vitamin D than those in the control group (28.5 ± 9.5 ng/ml vs. 29.9 ± 10.2 ng/ml, P = 0.018). Subjects with serum vitamin D deficiency or insufficiency had higher odds for MS than those with sufficient vitamin D levels [deficiency vs. sufficiency, adjusted odds ratio (aOR) =1.860 (95% CI = 1.234-2.804), P = 0.003; insufficiency vs. sufficiency, aOR = 1.669 (95% CI = 1.237-2.251), P = 0.001]. Similarly, subjects in the lowest quartile of vitamin D had higher odds for MS than those in the highest quartile of vitamin D (aOR = 2.792, 95% CI = 1.719-4.538, P < 0.001). Vitamin D level was positively correlated with age and male, but negatively correlated with serum leptin level. CONCLUSION: Subjects with low vitamin D level had higher odds for MS, but higher levels of leptin, compared to those with high vitamin D levels.

Diagnostic pitfalls and therapeutic outcomes of the macrofollicular variant of papillary thyroid carcinoma.

BACKGROUND: The macrofollicular variant of papillary thyroid cancer (MFVPTC) is a rare histological variant of papillary thyroid cancer (PTC), with only 71 cases reported through 2014. This study analyzed the clinical, preoperative thyroid ultrasonography (US), and fine needle aspiration cytology (FNAC) features; and therapeutic outcomes of 11 patients with MFVPTC. METHODS: The records of 393 patients with histologically diagnosed follicular variant of papillary thyroid carcinoma (FVPTC), including 11 with MFVPTC, were retrospectively reviewed. Preoperative thyroid US findings, clinical presentation, treatment outcomes, and survival rates were analyzed. RESULT: Mean tumor size was significantly greater in patients with MFVPTC than that in those with FVPTC (4.2 ± 2.1 cm vs. 2.9 ± 1.7 cm; p = 0.016). No patient with MFVPTC had lymph node involvement, but one had a micrometastasis to the lung, which responded well to therapeutic radioiodine. All MFVPTC lesions were isoechoic on US. Eight nodules had calcifications and eight had irregular margins. FNAC showed that these tumors had low cellularity, absence or focal presence of enlarged clear nuclei, and subtle or focal nuclear features of PTC. Cells were, arranged in microfollicular pattern, with abundant colloid background. Multifocal PTCs were detected in the opposite lobe of two patients. All 11 patients with MFVPTC had excellent outcomes. No patient experienced recurrence, and survival rates were high. CONCLUSIONS: Malignant US criteria combined with FNAC features have a low preoperative diagnostic rate for MFVPTC. Surgery is recommended for patients with thyroid nodules larger than 4 cm and those with subtle and focal atypical nuclei in FNAC.

Interferon α-inducible protein 27 is an oncogene and highly expressed in cholangiocarcinoma patients with poor survival.

OBJECTIVE: Cholangiocarcinoma (CCA) is a devastating disease. Interferon α-inducible protein 27 (IFI27), originally known to involve in innate immunity, is later found to intervene in cell proliferation, leading to inventive studies regarding the role of IFI27 in cancer treatment. We aimed to investigate the role of IFI27 in CCA. MATERIALS AND METHODS: Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofluorescent and immunohistochemical stains, and xenograft animal model were applied. RESULTS: IFI27 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI27 knockdown attenuated CCA cell migration and invasion through inhibition of epithelial-mesenchymal transition, which was supported by increased E-cadherin and decreased N-cadherin and fibronectin. Filamentous actin level was also reduced. IFI27 knockdown further repressed expression and secretion of vascular endothelial growth factor (VEGF-A), a strong stimulator of angiogenesis, through downregulation of c-jun and c-fos, which was supported in vitro by the finding that human vascular endothelial cells grew more slowly in conditioned medium of IFI27 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI27 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI27 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI27 expression was linked to inferior overall survival of CCA patients. CONCLUSION: Our data strongly suggest that IFI27 could be deemed as a potential target for CCA treatment.

Status of bone strength and factors associated with vertebral fracture in postmenopausal women with type 2 diabetes.

OBJECTIVE: The aim of this study was to assess the status of bone mass, microarchitecture, and factors associated with vertebral fracture in postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: We consecutively enrolled 285 women (aged 60.7 ±â€Š6.9 y) with T2DM who underwent bone mineral density (BMD) and trabecular bone score (TBS) assessment using dual-energy x-ray absorptiometry; T8-S1 lateral spine radiographs; laboratory evaluation; and interviews regarding clinical risk factors based on the fracture risk assessment tool (FRAX). RESULTS: Low bone mass and deteriorated bone microarchitecture were observed in 63.2% and 72.6% of women with T2DM, respectively. TBS was correlated with lumbar spine, femoral neck, and total hip BMD. Significant differences in TBS were observed between the normal BMD, osteopenia, and osteoporosis groups. Age, vertebral fracture, and bone-specific alkaline phosphatase significantly differed among groups with different T scores or those classified by TBS categories. Bone-specific alkaline phosphatase was inversely correlated with BMD and TBS but positively with glycated hemoglobin. BMD showed a weaker correlation with vertebral fracture than TBS, TBS and BMD, FRAX, and TBS-adjusted FRAX. CONCLUSIONS: Low bone mass and deteriorated TBS were noted in approximately two-thirds of T2DM women and was also associated with vertebral fracture. In addition to aging, poor glycemic control may play an important role in bone remodeling, which may be associated with changes in bone strength in T2DM women. Bone strength together with clinical risk factors has the strongest association with fracture, and may potentially be useful to identify women with T2DM at risk.

The efficacy of radioactive iodine for the treatment of well-differentiated thyroid cancer with distant metastasis.

OBJECTIVE: Radioactive iodine (I) has been used as a treatment for high-risk well-differentiated thyroid cancer after thyroidectomy. The aim of this study was to evaluate the long-term follow-up results after using high accumulated doses of I (>600 mCi) for the treatment of well-differentiated thyroid cancer. PATIENTS AND METHODS: In this study, we retrospectively evaluated prospectively enrolled patients with well-differentiated thyroid cancer who were treated and followed up in Chang Gung Memorial Hospital in Linkou and Keelung, Taiwan. All the patients underwent thyroidectomy between 1979 and 2016. RESULTS: For our study, 228 patients with papillary and follicular thyroid carcinoma with distant metastases were enrolled. Of the 228 patients, 71 (31.1%) received I therapy with an accumulated dose of at least 600 mCi. Forty-four died because of disease-specific mortality (DSM) after a mean follow-up of 10.6±6.3 years. Compared with the patients in the DSM group, which included 27 survival cases, patients who were younger, and those with a multifocal tumor, more extensive thyroidectomy, and papillary thyroid carcinoma showed better prognosis. The DSM group included a higher percentage of patients who developed a secondary primary cancer after receiving a diagnosis of thyroid cancer than the survival group (18.2 vs. 3.7%). However, the difference did not reach statistical significance (P=0.075). CONCLUSION: I provided an effective therapeutic modality for well-differentiated thyroid cancer patients with distant metastasis. After a mean of follow-up 10 years, more than 60% of cases resulted in DSM when high accumulated I doses were administered.

MART-10, a 1α,25(OH)2D3 Analog, Potently Represses Metastasis of ER+ Breast Cancer Cells with VEGF-A Overexpression.

BACKGROUND: Breast cancer ranks second in the list of cancer-related deaths for women. Even under multidisciplinary treatment, 25-50% of patients with breast cancer still ultimately develop metastasis, leading to poor prognosis. In addition to inducing angiogenesis, vascular endothelial growth factor-A (VEGF-A) is believed to directly increase cancer cell metastatic potential and overexpression of VEGF-A is associated with higher invasiveness of breast cancer. 1α,25(OH)2D3, the active form of vitamin D, and its analogs have been widely applied as anticancer agents in the past. MATERIAL AND METHODS: Western blot, migration and invasion assays, enzyme-linked immunosorbent assay, and immunofluorescent stain were applied in this study. RESULT: VEGF-A increased cell migration and invasion in estrogen receptor-positive (ER+) breast cancer MCF-7 cells. VEGF-A induced an autocrine loop in MCF-7 cells as VEGF-A treatment increased both VEGF-A expression and secretion. The expression of VEGF receptor type 2 (VEGFR2) and neuropilin 1 was also up-regulated by VEGF-A in MCF-7 cells. In addition, F-actin synthesis and LIM domain kinase 1 (LIMK-1) phosphorylation were increased by VEGF-A. VEGF-A also increased ß-catenin expression and nuclear translocation of both ß-catenin and nuclear factor-ĸB (NF-ĸB), indicating increased ß-catenin and NF-ĸB activity. 1α,25(OH)2D3 and MART-10, an analog of 1α,25(OH)2D3, effectively repressed VEGF-A-induced MCF-7 cell migration and invasion and other VEGF-A-induced effects on MCF-7 cells, with MART-10 being more potent than 1α,25(OH)2D3 Conclusion: MART-10 can be deemed as a promising agent for prevention and treatment of metastasis of ER+ breast cancer with VEGF-A overexpression.

A community-based study on the association between Helicobacter pylori Infection and obesity.

Helicobacter pylori (H. pylori) infection can induce chronic inflammation and is associated with insulin resistance, metabolic syndrome and body mass index (BMI, kg/m2) changes. This study aimed to evaluate the association between H. pylori infection and overweight/obesity. This research was a cross-sectional study conducted from March 2014 to November 2016, using data from the three districts in the northeastern region of Taiwan. The inclusion criteria were an age >30 years and the absence of pregnancy. Ultimately, 2686 subjects (1713 women) were included in this study. Among the subjects aged less than 50 years, the subjects with H. pylori infection had higher mean BMI values than those without H. pylori infection (40-49 years: 25.7 ± 4.4 vs. 24.7 ± 3.8, P = 0.025; 30-39 years: 24.9 ± 4.4 vs. 24.0 ± 4.1, P = 0.063). H. pylori infection increased the risk of being obese 2 (BMI ≥30) (odds ratio, OR = 1.836, 95% CI = 1.079-3.125, P = 0.025) with adjustments for demographic factors in subjects aged less than 50 years. In conclusions, subjects with H. pylori infection and age less than 50 years may increase a risk of being obesity (BMI ≥30) compared to those without this type of infection.

Differentiation of the Follicular Variant of Papillary Thyroid Carcinoma From Classic Papillary Thyroid Carcinoma: An Ultrasound Analysis and Complement to Fine-Needle Aspiration Cytology.

OBJECTIVES: It is difficult to establish a diagnosis of the follicular variant of papillary thyroid carcinoma (PTC) using fine-needle aspiration cytology (FNAC). Preoperative features on ultrasound (US) imaging are different between follicular PTC and classic PTC. This study developed a risk score system to differentiate follicular PTC from classic PTC and to correlate the risk score of follicular PTC with its FNAC categories and pathologic features. METHODS: The US features, FNAC results, and pathologic reports of 156 follicular PTC nodules and 152 classic PTC nodules from 296 patients with PTC along with their clinical characteristics were reviewed retrospectively. A risk score system based on US features was developed by multivariate logistic regression to differentiate classic PTC from follicular PTC nodules. The risk scores were then correlated with the FNAC category and pathologic features of the nodules. RESULTS: The US risk score (5 × echogenicity + 3 × calcifications + 3 × marginal regularity) had an area under the receiver operating characteristic curve of 0.85 and a cutoff value of 8.0, with specificity of 87% and sensitivity of 69% for predicting a classic PTC nodule. The follicular PTC nodules with low Bethesda categorization (I-III) had a median US risk score of 6 (range, 0-11), which was higher than that of nodules with high categorization (IV-VI; median, 3; range, 0-11). CONCLUSIONS: The US risk score may be useful in differentiating classic PTC from follicular PTC and complementary to FNAC in identifying follicular PTC.

1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Metastasis After VEGF-A Stimulation.

AIMS: Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)2D3) analog, on PanNET cell metastasis after VEGF-A stimulation. MATERIALS AND METHODS: Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study. RESULTS: VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)2D3 and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)2D3 and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)2D3 and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)2D3 and MART-10. CONCLUSION: Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.

Higher body weight and distant metastasis are associated with higher radiation exposure to the household environment from patients with thyroid cancer after radioactive iodine therapy.

There were insufficient data regarding radiation exposure to the household environment from patients with thyroid cancer who received radioactive iodine (RAI) therapy in Asia; we therefore performed the present study at the Chang Gung Memorial Hospital in Keelung, Taiwan.Patients with papillary or follicular thyroid cancer who received 3.7 GBq (100 mCi) RAI were enrolled in this prospective hospital-based study. The enrolled patients were asked to place a thermoluminescent dosimeter in the living room, bedroom, and bathroom of their houses for 4 weeks to measure radiation exposure to the household environment.A total of 43 patients (18 men and 25 women; mean age 51 ±â€Š13 years) who received 3.7 GBq (100 mCi) RAI completed the study. The mean value of total radiation exposure over 4 weeks from the patients to the bedroom, bathroom, and living room (eliminating the background radiation factor) was 0.446 ±â€Š0.304 (0.088-1.382) mSv. We divided the patients into 2 groups: those with more than and less than the mean value of total radiation exposure to the bedroom, bathroom, and living room. Factors associated with the higher amount of radiation exposure from the patients to the household environment were patient body weight (P = .025, univariate analysis; P = .037, multivariate analysis, odds ratio [95% confidence interval] 1.067 [1.004-1.134]) and distant metastases based on I post-therapy scanning (P = .041, univariate analysis; P = .058, multivariate analysis, odds ratio [95% confidence interval] 6.453 [0.938-44.369]); age, sex, body mass index, renal function, serum stimulated thyroglobulin level, and recombinant human thyroid-stimulating hormone use were not associated with the amount of radiation exposure from the patients to the household environment.Higher body weight and distant metastases may be the best predictors for higher radiation exposure to the household environment from patients with thyroid cancer after RAI therapy.

Therapeutic Outcomes of Patients with Multifocal Papillary Thyroid Microcarcinomas and Larger Tumors.

A retrospective review of 626 patients with multifocal papillary thyroid carcinoma (PTC) including 147 patients (23.5%) with multifocal papillary thyroid microcarcinoma (PTMC) from a total of 2,536 patients with PTC who visited the Chang Gung Medical Center in Linkou, Taiwan, was performed. A comparison of the clinical features between 626 multifocal and 1,910 solitary PTC cases showed that patients in the multifocal PTC group were older and had a smaller mean tumor size, a more advanced tumor-node-metastasis (TNM) stage, and a higher percentage of nonremission status compared to patients in the solitary PTC group. Of the 626 patients with multifocal PTC, the group with larger tumors showed a more advanced TNM stage, a higher percentage of lymph node metastasis and soft tissue invasion, and a higher nonremission rate compared to the multifocal PTMC group. Of the 626 patients with multifocal PTC, 25 patients (4%) died during a mean follow-up period of 7.1 ± 5.3 years. Kaplan-Meier survival curves showed a significantly lower survival rate associated with multifocal PTMC compared to that with solitary PTMC.

Analysis of the associations among Helicobacter pylori infection, adiponectin, leptin, and 10-year fracture risk using the fracture risk assessment tool: A cross-sectional community-based study.

Helicobacter pylori (H. pylori) infection may induce inflammatory cytokines or adipokines that influence bone turnover and bone fracture risk. This study aimed to evaluate the association among H. pylori infection, adipokines, and 10-year fracture risk using the Fracture Risk Assessment Tool scale. From August 2013 to February 2016, a community-based cohort was surveyed by Keelung Chang-Gung Memorial Hospital. Subjects were included if they were older than 40 years and not pregnant. All participants underwent a standardized questionnaire survey, physical examination, urea breath test, and blood tests. A total of 2,689 participants (1,792 women) were included in this cross-sectional study. In both sexes, participants with a high fracture risk were older and had higher adiponectin values than participants without a high fracture risk (mean age, female: 72.9 ± 5.6 vs. 55.8 ± 7.3 years, P < 0.0001; male: 78.9 ± 4.7 vs. 58.1 ± 8.9 years, P < 0.001) (adiponectin, female: 10.8 ± 6.3 vs. 8.7 ± 5.2 ng/ml, P < 0.001; male: 9.7 ± 6.1 vs. 5.5 ± 3.8 ng/ml, P < 0.001). Adiponectin was correlated with high fracture risk in both sexes, but H. pylori infection and leptin was not. In logistic regression analysis, adiponectin could not predict high fracture risk when adjusting the factor of body mass index (BMI) in men group. In conclusion, H. pylori infection and leptin could not predict 10-year fracture risk in either sex. Adiponectin was correlated with bone fracture risk in both sexes and the correlation might be from the influence of BMI.

Prognosis of papillary thyroid cancers with positive serum thyroglobulin antibody after total thyroidectomy.

BACKGROUND/OBJECTIVE: To investigate the influence of serum anti-thyroglobulin antibody (TgAb) on the prognosis in papillary thyroid cancer (PTC) patients. METHODS: In this retrospective study, the participants were enrolled from 1206 PTC patients (927 women, 279 men; mean age, 42.2 years) with T2 and higher, or N1 or M1 classifications in tumor-node-metastasis staging after total thyroidectomy. We recorded the final serum TgAb data (on thyroxin therapy) at the end of follow-up in 2012. Patients were classified as negative TgAb or positive TgAb groups on the basis of their serum TgAb levels (< 70 IU/mL or ≥ 70 IU/mL). RESULTS: Among the 1206 patients, after mean follow-up for 11.6 ± 6.1 years (range, 2.0-29.2 years), there were 75 with positive TgAb and 1131 with negative TgAb. Patient categorization depending on the follow-up time (2-5 years after surgery, 5-10 years after surgery, and 10-30 years after surgery) was performed. In comparison to traditional risk factors, such as age, tumor size, and sex, which were important prognostic factors for cancer recurrence and mortality in PTC patients, there was no significant difference in the prognosis between positive TgAb patients and negative TgAb patients by the multivariate analyses (cancer recurrence, p = 0.164, p = 0.112, p = 0.202, respectively; cancer mortality, p = 0.181, p = 0.646, p = 0.656, respectively) based on the different follow-up times. CONCLUSION: Positive serum TgAb was not a risk factor, and was not associated with the prognosis of PTC patients.

Association between metabolic syndrome and bone fracture risk: A community-based study using a fracture risk assessment tool.

Osteoporosis and metabolic syndrome (MS) share similar risk factors. Previous studies of association between bone marrow density (BMD) and MS are controversial. Moreover, some studies revealed that MS is associated with BMD but not with bone fracture. In clinical practice, patients pay more attention to bone fracture risk than BMD values. Hence, this study aimed to evaluate the association between MS and the 10-year bone fracture risk probability using a fracture risk assessment tool (FRAX) from community-based data. From March 2014 to August 2015, 2689 participants (897 men and 1792 women) were enrolled in this study. Inflammatory cytokines, such as tumor necrosis factor alpha and C-reactive protein, and adipokines were included for analysis.The mean age was 60.2 ±â€Š10.7 years in men and 58.9 ±â€Š9.6 years in women. The percentage of MS was 27.6% in men and 27.9% in women. Participants were divided into 2 groups, those with or without MS. Compared with women without MS, women with MS had a higher rate of fracture risk (22.8% vs 16.3%, P = .001). In contrast, men with MS had a lower rate of fracture risk then men without MS (5.6% vs 12.3%, P = .004). However, MS loss the association with a high bone fracture risk in men based on multivariate logistical regression analysis, after adjusting for confounding factor of body mass index (BMI). Conclusively, the result of regression analysis between MS and the bone fracture risk may be different in men and women, and BMI was an important confounding factor to interfere with the regression analysis.

25(OH)D Is Effective to Repress Human Cholangiocarcinoma Cell Growth through the Conversion of 25(OH)D to 1α,25(OH)2D3.

Cholangiocarcinoma (CCA) is a devastating disease without effective treatments. 1α,25(OH)2D3, the active form of Vitamin D, has emerged as a new anti-cancer regimen. However, the side effect of hypercalcemia impedes its systemic administration. 25(OH)D is biologically inert and needs hydroxylation by CYP27B1 to form 1α,25(OH)2D3, which is originally believed to only take place in kidneys. Recently, the extra-renal expression of CYP27B1 has been identified and in vitro conversion of 25(OH)D to 1α,25(OH)2D3 has been found in some cancer cells with CYP27B1 expression. In this study, CYP27B1 expression was demonstrated in CCA cells and human CCA specimens. 25(OH)D effectively represses SNU308 cells growth, which was strengthened or attenuated as CYP27B1 overexpression or knockdown. Lipocalcin-2 (LCN2) was also found to be repressed by 25(OH)D. After treatment with 800 ng/mL 25(OH)D, the intracellular 1α,25(OH)2D3 concentration was higher in SNU308 cells with CYP27B1 overexpression than wild type SNU308 cells. In a xenograft animal experiment, 25(OH)D, at a dose of 6 µg/kg or 20 µg/kg, significantly inhibited SNU308 cells' growth without inducing obvious side effects. Collectively, our results indicated that SNU308 cells were able to convert 25(OH)D to 1α,25(OH)2D3 and 25(OH)D CYP27B1 gene therapy could be deemed as a promising therapeutic direction for CCA.

PTEN Insufficiency Increases Breast Cancer Cell Metastasis In Vitro and In Vivo in a Xenograft Zebrafish Model.

BACKGROUND/AIM: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) insufficiency is commonly found in breast cancer patients with metastasis. We investigated the mechanisms by which PTEN affects breast cancer metastatic behavior. MATERIALS AND METHODS: Migration and invasion assay, western blot, immunofluorescent staining and zebrafish animal model were applied. RESULTS: We showed that PTEN insufficiency induced an increase in MCF-7 cell migration and invasion through induction of epithelial-mesenchymal transition (EMT), which was triggered by up-regulation of the EMT-inducing transcriptional factors Zeb1, Zeb2, Snail, Slug and Twist. Simultaneously, E-cadherin expression was inhibited and P-cadherin was up-regulated. Further, WNT1 inducible signaling pathway protein 1 (WISP1) and lipocalin-2 (LCN2) expressions were increased after PTEN knockdown in MCF-7 cells, which also exhibited increased filamentous actin (F-actin) synthesis and extracellular matrix metalloproteinase-2 (MMP-2) and MMP-9 expression. We further showed that PTEN knockdown in MCF-7 cells could increase cell migration in the xenograft zebrafish model. CONCLUSION: Our findings reveal new therapeutic targets for breast cancer patients with PTEN insufficiency.

1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Growth Through Induction of G0/G1 Cell-cycle Arrest and Apoptosis.

BACKGROUND: Neuroendocrine tumors (NETs) are the second most common digestive malignancy. For advanced NETs, survival is not satisfactory. Vitamin D has emerged as a promising anticancer drug. MATERIALS AND METHODS: Cell proliferation assay, western blot, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were applied. RESULTS: We demonstrated that RIN-m cells, neuroendocrine tumor cells, expressed vitamin D receptor (VDR) and VDR expression increased with increasing exposure to 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] or MART-10, a 1α,25(OH)2D3 analog. MART-10 had anti-growth effect on RIN-m cells comparable to those of 1α,25(OH)2D3 The growth inhibition of both drugs was mediated by induction of cell-cycle arrest at G0/G1 phase and apoptosis. Western blot assay further revealed that this G0/G1 arrest was due to the up-regulation of p27 and down-regulation of cyclin dependent kinase 4 (CDK4), with MART-10 also reducing CDK6. Apoptosis induction was further supported by increased cleaved caspase-3 expression after treatment. CONCLUSION: MART-10 appears to be a promising regimen for NET treatment.

The Associations Between Helicobacter pylori Infection, Serum Vitamin D, and Metabolic Syndrome: A Community-Based Study.

The associations between Helicobacter pylori infection, serum vitamin D level, and metabolic syndrome (MS) are controversial. The present community-based study aimed to investigate the effect of H pylori infection and serum vitamin D deficiency on MS development.Individuals from the northeastern region of Taiwan were enrolled in a community-based study from March, 2014 to August, 2015. All participants completed a demographic survey and underwent the urea breath test (UBT) to detect H pylori infection as well as blood tests to determine levels of vitamin D, adiponectin, leptin, and high-sensitivity C-reactive protein. The ATP III criteria for MS were used in this study.A total of 792 men and 1321 women were enrolled. The mean age was 56.4 ±â€Š13.0 years. After adjusting for age and sex, the estimated odds of MS development for a UBT-positive subject were 1.503 (95% confidence interval [CI]: 1.206-1.872, P < 0.001) when compared to a UBT-negative subject. For participants with vitamin D deficiency (<20 ng/mL), the odds of MS development were 1.423 (95% CI: 1.029-1.967, P = 0.033) when compared to those with sufficient vitamin D level (>30 ng/mL). For participants with both H pylori infection and vitamin D deficiency, the odds of MS development were 2.140 (95% CI: 1.348-3.398, P = 0.001) when compared to subjects without H pylori infection and with sufficient vitamin D levels.H pylori infection and vitamin D deficiency could be predictors of MS. For individuals with both H pylori infection and vitamin D deficiency, the odds of MS development were 2.140 when compared to individuals without H pylori infection and with sufficient vitamin D levels.

The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential.

Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), the newly-synthesized 1α,25(OH)2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.