Joshua Vorstenbosch

The TGF-β co-receptor, CD109, promotes internalization and degradation of TGF-β receptors

Transforming growth factor-β (TGF-β) is implicated in numerous pathological disorders, including cancer and mediates a broad range of biological responses by signaling through the type I and II TGF-β receptors. Internalization of these receptors via the clathrin-coated pits pathway facilitates SMAD-mediated signaling, whereas internalization via the caveolae pathway is associated with receptor degradation. Thus, molecules that modulate receptor endocytosis are likely to play a critical role in regulating TGF-β action. We previously identified CD109, a GPI-anchored protein, as a TGF-β co-receptor and a negative regulator of TGF-β signaling. Here, we demonstrate that CD109 associates with caveolin-1, a major component of the caveolae. Moreover, CD109 increases binding of TGF-β to its receptors and enhances their internalization via the caveolae. In addition, CD109 promotes localization of the TGF-β receptors into the caveolar compartment in the presence of ligand and facilitates TGF-β-receptor degradation. Thus, CD109 regulates TGF-β receptor endocytosis and degradation to inhibit TGF-β signaling. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Wound-healing with mechanically robust and biodegradable hydrogel fibers loaded with silver nanoparticles.

The objective of this study is to provide a novel synthetic approach for the manufacture of wound-healing materials using covalently cross-linked alginate fibers loaded with silver nanoparticles. Alginate fibers are prepared by wet-spinning in a CaCl(2) precipitation bath. Using this same approach, calcium cross-links in alginate fibers are replaced by chemical cross-links that involve hydroxyl groups for subsequent cross-linking by glutaraldehyde. The cross-linked fibers become highly swollen in aqueous solution due to the presence of carboxyl functional groups, and retain their mechanical stability in physiological fluids owing to the stabilized network of covalent bonds. Alginate fibers can then be loaded with silver ions via the ion-exchange reaction. Silver ions are reduced to yield 11 nm silver nanoparticles incorporated in the polymer gel. This method provides a convenient platform to incorporate silver nanoparticles into alginate fibers in controlled concentrations while retaining the mechanical and swelling properties of the alginate fibers. Our study suggests that the silver nanoparticles loaded fibers may be easily applied in a wound healing paradigm and promote the repair process though the promotion of fibroblast migration to the wound area, reduction of the inflammatory phase, and the increased epidermal thickness in the repaired wound area, thereby improving the overall quality and speed of healing.

Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing.

Transforming growth factor‐β (TGF‐β) is a multifunctional growth factor involved in all aspects of wound healing. TGF‐β accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol‐anchored protein, as a novel TGF‐β coreceptor and inhibitor of TGF‐β signaling in vitro. To determine the effects of CD109 in vivo on wound healing, we generated transgenic mice overexpressing CD109 in the epidermis. In excisional wounds, we show that CD109 transgenic mice display markedly reduced macrophage and neutrophil recruitment, granulation tissue area, and decreased Smad2 and Smad3 phosphorylation, whereas wound closure remains unaffected as compared with wild‐type littermates. Futhermore, we demonstrate that the expression of the proinflammatory cytokines interleukin‐1α and monocyte chemoattractant protein‐1, and extracellular matrix components is markedly decreased during wound healing in CD109 transgenic mice. In incisional wounds, CD109 transgenic mice show improved dermal architecture, whereas the tensile strength of the wound remains unchanged. Taken together, our findings demonstrate that CD109 overexpression in the epidermis reduces inflammation and granulation tissue area and improves collagen organization in vivo.

Living with a Unilateral Mastectomy Defect: A Utility Assessment and Outcomes Study

BACKGROUND The gold standard for the treatment of breast cancer includes mastectomy surgery. Our goal was to quantify the health state utility assessment of living with unilateral mastectomy. METHODS The visual analogue scale (VAS), time trade-off (TTO), and standard gamble (SG) were used to obtain utilities for unilateral mastectomy, monocular blindness and binocular blindness from a prospective sample of the general population and medical students. RESULTS All measures (VAS, TTO, SG) for unilateral mastectomy (0.75 SD 0.17, 0.87 SD 0.14, and 0.86 SD 0.18, respectively) of the 140 volunteers were significantly different from the corresponding scores for monocular (0.61 SD 0.18, 0.84 SD 0.17, and 0.84 SD 0.18, respectively) and binocular blindness (0.38 SD 0.17, 0.67 SD 0.24, and 0.69 SD 0.23, respectively). Age, gender, race, education, and income were not statistically significant independent predictors of utility scores. CONCLUSION In a sample of the general population and medical students, utility assessments for living with unilateral mastectomy were comparable with those of living with bilateral mastectomy and severe breast hypertrophy. Our sample population, if faced living with unilateral mastectomy was willing to gamble a theoretical 14% chance of death and willing to trade 4.2 years of existing life-years.

Brief Report: CD109 Overexpression Ameliorates Skin Fibrosis in a Mouse Model of Bleomycin-Induced Scleroderma

OBJECTIVE Transforming growth factor β (TGFβ) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGFβ signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGFβ coreceptor and have shown that it antagonizes TGFβ signaling and TGFβ-induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin-induced SSc. METHODS Transgenic mice overexpressing CD109 in the epidermis and their wild-type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Massons trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGFβ signaling was examined by determining phospho-Smad2 and phospho-Smad3 levels using Western blotting and immunohistochemistry. RESULTS Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycin-induced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels, as compared to their WT littermates. CONCLUSION Our findings suggest that CD109 inhibits TGFβ signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal-epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma.

Nipple-areolar Complex Reconstruction following Postmastectomy Breast Reconstruction: A Comparative Utility Assessment Study

Background: Nipple-areola complex (NAC) reconstruction occurs toward the final stage of breast reconstruction; however, not all women follow through with these procedures. The goal of this study was to determine the impact of the health state burden of living with a reconstructed breast before NAC reconstruction. Methods: A sample of the population and medical students at McGill University were recruited to establish the utility scores [visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG)] of living with an NAC deformity. Utility scores for monocular and binocular blindness were determined for validation and comparison. Linear regression and Student’s t test were used for statistical analysis, and significance was set at P < 0.05. Results: There were 103 prospective volunteers included. Utility scores (VAS, TTO, and SG) for NAC deformity were 0.84 ± 0.18, 0.92 ± 0.11, and 0.92 ± 0.11, respectively. Age, gender, and ethnicity were not statistically significant independent predictors of utility scores. Income thresholds of <

Thigh laxity after massive weight loss: a utilities outcomes assessment.

10,000 and >

Population preferences of undergoing brachioplasty for arm laxity.

10,000 revealed a statistically significant difference for VAS (P = 0.049) and SG (P = 0.015). Linear regression analysis showed that medical education was directly proportional to the SG and TTO scores (P < 0.05). Conclusions: The absence of NAC in a reconstructed breast can be objectively assessed using utility scores (VAS, 0.84 ± 0.18; TTO, 0.92 ± 0.11; SG, 0.92 ± 0.11). In comparison to prior reported conditions, the quality of life in patients choosing to undergo NAC reconstruction is similar to that of persons living with a nasal deformity or an aging neck requiring rejuvenation.

Heparin-induced thrombocytopenia and thrombosis as an under-diagnosed cause of flap failure in heparin-naive patients: a case report and systematic review of the literature.

BackgroundThe presence of excess skin after massive weight loss, particularly in the thighs, not only contributes to a negative body image but can also lead to functional deficits in mobility. In the present study, we quantified the health state utility of living with excess skin in the thighs in an attempt to objectively establish the burden on the quality of life in patients living with excess thigh skin laxity. MethodUsing visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG), we compared the utility outcome scores for thigh skin excess with monocular and binocular blindness from a prospective sample of medical students and the general population. Utility scores were compared using paired t test. Linear regression was performed using age, race, and education as independent predictors of each of the utility scores. ResultsOne hundred thirty-four prospective participants were enrolled during a 6-month period, and 112 participants met our inclusion criteria. The utility outcome scores for thigh lift (VAS, TTO, and SG, 0.77 ± 0.15, 0.90 ± 0.11, and 0.89 ± 0.14, respectively) were statistically different from binocular blindness (VAS, TTO, and SG, 0.37 ± 0.18, 0.70 ± 0.23, and 0.70 ± 0.26; P < 0.001), but other than VAS (0.67 ± 0.15, P < 0.001), similar to monocular blindness (TTO and SG, 0.89 ± 0.13 and 0.81 ± 0.14, respectively; P > 0.05). SG (0.89 ± 0.14 vs 0.97 ± 0.02, P = 0.003) and TTO (0.89 ± 0.11 vs 0.95 ± 0.03, P = 0.038) were different between general population and medical students, respectively, corresponding to 3.96 versus 1.80 potential years willing to be traded (P < 0.05). Additionally, SG was higher in whites versus nonwhites who were willing to take a potential 8% chance of mortality compared to 15%, respectively (P = 0.001), to achieve “perfect” health. ConclusionsWe have objectified the utility of living with thigh deformity after massive weight loss. Our sample population if faced with the condition was willing to sacrifice a potential 3.6 years of life and potentially undergo a procedure with 11% chance of mortality to address excess thigh laxity.

CD109, a novel TGF-β antagonist, decreases fibrotic responses in a hypoxic wound model

BackgroundThe number of patients requesting surgical procedures performed for brachioplasty and massive weight loss is increasing. The authors set out to quantify the health state utility outcome assessment of living with arm deformity requiring brachioplasty. MethodsUtility assessments using the visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG) were used to obtain utilities scores for arm deformity, monocular blindness, and binocular blindness from a sample of the general population and medical students. Linear regression and Student t test were used for statistical analysis. A P value less than 0.05 was deemed statistically significant. ResultsAll the measures for arm deformity of the 107 volunteers (VAS, 0.80 ± 0.14; TTO, 0.91 ± 0.12; SG, 0.94 ± 0.10) were significantly different (P < 0.001) from the corresponding measures for monocular blindness and binocular blindness. When compared to the sample of the general population, having a medical education demonstrated a statistical significance of being less likely to trade years of life and less likely to gamble risk of death for a procedure such as a brachioplasty. Race and sex were not statistically significant independent predictors of risk acceptance. ConclusionsWe have objectified the health state of living with upper arm deformity requiring brachioplasty. Utility outcome scores (VAS, 0.80 ± 0.14; TTO, 0.91 ± 0.12; SG, 0.94 ± 0.10) were comparable to living with health states such as aging neck needing rejuvenation, excess skin in the thighs necessitating thigh lift, and massive weight loss requiring panniculectomy based on previously reported studies.