The interplay of matrix metalloproteinase-8, transforming growth factor-beta 1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

Background: Matrix metalloproteinase-8 (MMP-8) has oncosuppressive properties in various cancers. We attempted to assess MMP-8 function in oral tongue squamous cell carcinoma (OTSCC). Methods: MMP-8 overexpressing OTSCC cells were used to study the effect of MMP-8 on proliferation, apoptosis, migration, invasion and gene and protein expression. Moreover, MMP-8 functions were assessed in the orthotopic mouse tongue cancer model and by immunohistochemistry in patient samples. Results: MMP-8 reduced the invasion and migration of OTSCC cells and decreased the expression of MMP-1, cathepsin-K and vascular endothelial growth factor-C (VEGF-C). VEGF-C was induced by transforming growth factor-beta 1 (TGF-beta 1) in control cells, but not in MMP-8 overexpressing cells. In human OTSCC samples, low MMP-8 in combination with high VEGF-C was an independent predictor of poor cancer-specific survival. TGF-beta 1 treatment also restored the migration of MMP-8 overexpressing cells to the level of control cells. In mouse tongue cancer, MMP-8 did not inhibit metastasis, possibly because it was eliminated in the peripheral carcinoma cells. Conclusions: The suppressive effects of MMP-8 in OTSCC may be mediated through interference of TGF-beta 1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.Peer reviewe

Low free 25-hydroxyvitamin D and high vitamin D binding protein and parathyroid hormone in obese Caucasians. A complex association with bone?

Background Studies have shown altered vitamin D metabolism in obesity. We assessed differences between obese and normal-weight subjects in total, free, and bioavailable 25-hydroxyvitamin D (25(OH) D, 25(OH) D-Free, and 25(OH) D-Bio, respectively), vitamin D binding protein (DBP), parathyroid hormone (PTH) and bone traits. Methods 595 37-47-year-old healthy Finnish men and women stratified by BMI were examined in this cross-sectional study. Background characteristic and intakes of vitamin D and calcium were collected. The concentrations of 25(OH) D, PTH, DBP, albumin and bone turnover markers were determined from blood. 25(OH) D-Free and 25(OH) D-Bio were calculated. pQCT was performed at radius and tibia. Results Mean +/- SE (ANCOVA) 25(OH) D-Free (10.8 +/- 0.6 vs 12.9 +/- 0.4 nmol/L; P = 0.008) and 25(OH) DBio (4.1 +/- 0.3 vs 5.1 +/- 0.1 nmol/L; P = 0.003) were lower in obese than in normal-weight women. In men, 25(OH) D (48.0 +/- 2.4 vs 56.4 +/- 2.0 nmol/L, P = 0.003), 25(OH) D-Free (10.3 +/- 0.7 vs 12.5 +/- 0.6 pmol/L; P = 0.044) and 25(OH) D-Bio (4.2 +/- 0.3 vs 5.1 +/- 0.2 nmol/L; P = 0.032) were lower in obese. Similarly in all subjects, 25(OH) D, 25(OH) D-Free and 25(OH) D-Bio were lower in obese (P Conclusions The associations between BMI and 25(OH) D, 25(OH) D-Free, and 25(OH) D-Bio, DBP, and PTH suggest that obese subjects may differ from normal-weight subjects in vitamin D metabolism. BMI associated positively with trabecular bone traits and CSI in our study, and slightly negatively with cortical bone traits. Surprisingly, there was a negative association of free and bioavailable 25(OH) D and some of the bone traits in obese women.Peer reviewe

Anti-Heparanase Aptamers as Potential Diagnostic and Therapeutic Agents for Oral Cancer

Peer reviewe

Elevated preoperative serum levels of collagen I carboxyterminal telopeptide predict better outcome in early-stage luminal-B-like (HER2-negative) and triple-negative subtypes of breast cancer

Abstract Type 1 collagen is an important part of the extracellular matrix and changes in its metabolism and distribution are essential in breast cancer induction and progression. Serum concentrations of type 1 collagen synthesis (aminoterminal propeptide (PINP)) and degradation markers (carboxyterminal telopeptide (ICTP)) have previously been studied in early and metastatic breast cancer, but no data are available on specific breast cancer subtypes. We assayed 662 preoperative serum samples for PINP and ICTP and 109 postoperative serum samples for ICTP. The results were linked to prospectively collected clinical data and the cases were divided into breast cancer subtypes for survival analyses. The concentrations of both pre- and postoperative ICTP serum levels increased linearly from ductal in situ carcinoma to stage I–II tumors, stage III tumors, and finally to those with concomitant primary metastases (preoperative ICTP, p = 0.009; postoperative ICTP, p = 0.016). High-preoperative ICTP levels were associated with better breast cancer-specific survival in connection with luminal-B-like (HER2-negative) tumors (p = 0.017), which was confirmed in Cox regression analysis (relative risk = 3.127; 95% confidence interval = 1.081–9.049, p = 0.035), when T-class (relative risk = 4.049; 95% confidence interval = 1.263–12.981; p = 0.019) and nodal status (relative risk = 3.896; 95% confidence interval = 1.088–13.959; p = 0.037) were included in the analysis. In patients with triple-negative breast cancer, a high-preoperative ICTP level was a significant predictor of local relapse-free survival in univariate (p = 0.0020) and multivariate analyses (relative risk = 13.04; 95% confidence interval = 1.354–125.5; p = 0.026; for T-class, relative risk = 2.128 and 95% confidence interval = 0.297–15.23; p = 0.452; for N-class, relative risk = 0.332 and 95% confidence interval = 0.033–3.307; p = 0.347). A preoperatively elevated serum ICTP level appears to be an important marker of better prognosis in triple-negative breast cancer and luminal-B-like (HER2-negative) subtypes

Rifampicin induces the bone form of alkaline phosphatase in humans

Abstract Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that regulates drug metabolism in the liver and intestine. In our clinical trials on healthy volunteers to discover novel metabolic functions of PXR activation, we observed that rifampicin, a well-established ligand for human PXR, 600 mg daily for a week, increased the plasma alkaline phosphatase (ALP) significantly compared with the placebo. Further analysis with lectin affinity electrophoresis revealed that especially the bone form of ALP was elevated. To investigate the mechanism(s) of bone ALP induction, we employed osteoblast lineage differentiated from human primary bone marrow–derived mesenchymal stromal cells. Rifampicin treatment increased ALP activity and mRNA level of bone biomarker genes (ALP, MGP, OPN and OPG). PXR expression was detected in the cells, but the expression was very low compared with the human liver. To further investigate the potential role of PXR in the ALP induction, we treated mice and rats with a rodent PXR ligand pregnenolone 16α-carbonitrile (PCN). However, PCN treatment did not increase plasma ALP activity or bone ALP mRNA expression. In conclusion, rifampicin treatment induces the bone form of ALP in the serum of healthy human volunteers. Further studies are required to establish the mechanism of this novel finding

New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties

Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype.Six AHR-knockout (Ahr-/-) and wild-type (Ahr+/+) mice of both genders were exposed to TCDD weekly for 10weeks, at a total dose of 200μg/kgbw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array.In Ahr+/+ mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr-/- mice displayed a slightly modified bone phenotype as compared with untreated Ahr+/+ mice, while TCDD exposure caused only a few changes in bones of Ahr-/- mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent.In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr+/+ mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations.© 2013 Elsevier Inc

Dietary phosphorus intake is negatively associated with bone formation among women and positively associated with some bone traits among men-a cross-sectional study in middle-aged Caucasians

High dietary phosphorus (P) intake has acute negative effects on calcium (Ca) and bone metabolism, but long-term clinical data are contradictory. We hypothesized that high P intake is associated with impaired bone health as suggested by earlier short-term studies on bone metabolism. In this cross-sectional study, we investigated associations between dietary P intake, bone traits in the radius and tibia, and bone turnover in a population-based sample of 37- to 47-year-old Caucasian premenopausal women (n = 333) and men (n = 179) living in Southern Finland (60 degrees N). We used various regression models in an "elaboration approach" to elucidate the role of P intake in bone traits and turnover. The addition of relevant covariates to the models mainly removed the significance of P intake as a determinant of bone traits. In the final regression model (P intake, weight, height, age, Ca intake, serum 25-hydroxyvitamin D, physical activity, smoking, contraceptive use in women), P intake was slightly positively associated only with bone mineral content and cross-sectional cortical bone area in the tibia of men. Among women, inclusion of Ca removed all existing significance in the crude models for any bone trait. In women P intake was negatively associated with the bone formation marker serum intact pro-collagen type I amino-terminal propeptide, whereas no association was present between P intake and bone turnover in men. In conclusion, these findings disagree with the hypothesis; P intake was not deleteriously associated with bone traits; however, P intake may negatively contribute to bone formation among women. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Autoimmune antibodies to collagen XIII in myasthenia gravis patients

Abstract Introduction: Evaluation of the nerve fascicular structure can be useful in diagnosing nerve damage, but it is a very challenging task with 3T MRI because of limited resolution. In this pilot study, we present the feasibility of high‐resolution 7T MRI for examining the nerve fascicular structure. Methods: A 3‐dimensional (3D) gradient‐spoiled sequence was used for imaging peripheral nerves in extremities. Images acquired with different in‐plane resolutions (0.42 × 0.42 mm vs. 0.12 × 0.12 mm), and different main field strengths (7T vs. 3T) were compared. Results: The individual nerve fascicles were identified at 0.12 × 0.12 mm resolution in both field strengths but not at 0.42 × 0.42 mm resolution. The fascicular structure was more sharply depicted in 7T images than in 3T images. Discussion: High‐resolution 3D imaging with 7T MRI demonstrated feasibility for imaging nerve fascicular structures