Wnt signalling and cancer stem cells

[Abstract] Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefly reviewed.Ministerio de Ciencia e Innovación; SAF2008-0060

A mathematical model of tissue factor-induced blood coagulation: discrete sites of initiation and regulation under conditions of flow

A mathematical model of blood coagulation under defined flow conditions, initiated and modulated by spatially discrete regions of surface bound tissue factor (TF) and thrombomodulin (TM), respectively, is presented. The model incorporates fluid phase and surface-associated reactions of the extrinsic, intrinsic, and common pathways, as well as three inhibitory pathways. The spatially heterogeneous model is formulated by finite element method, and an effective prothrombotic zone, which quantifies the spatial propagation of thrombin generation is defined. Characteristic features of coagulation are simulated under physiologic conditions, and the behavior of the system in response to perturbations in TF and TM surface densities, TF site dimensions, and wall shear rate is explored. The major findings of these studies include: (i) The model system responds in an 'all-or-none', threshold-like manner to changes in model parameters. (ii) It was found that prothrombotic effects may extend significantly beyond the dimensions of the spatially discrete site of TF expression in both axial and radial directions. (iii) The relationship between the length of the effective prothrombotic zone and the interval distance between tandem sites of TF expression dictate the net response of the system. Additive prothrombotic effects of sub-clinical lesions as well as suppressive antithrombotic effects of intervening TM-containing regions were observed. Secondly, the computational model is applied to calculate an individualized, systems-based metric of clotting potential for 210 pre-menopausal women in the Leiden Thrombophilia Study (LETS). The simulated variable was found to be a highly predictive parameter for deep venous thrombosis risk.Ph.D.Committee Chair: Chaikof, Elliot; Committee Member: Federspiel, William; Committee Member: Hanson, Stephen; Committee Member: McIntire, Larry; Committee Member: Voit, Eberhar

A Prospective Analysis of Dynamic Loss of Breast Projection in Tissue Expander-Implant Reconstruction

Background Breast projection is a critical element of breast reconstruction aesthetics, but little has been published regarding breast projection as the firm expander is changed to a softer implant. Quantitative data representing this loss in projection may enhance patient education and improve our management of patient expectations. Methods Female patients who were undergoing immediate tissue-expander breast reconstruction with the senior author were enrolled in this prospective study. Three-dimensional camera software was used for all patient photographs and data analysis. Projection was calculated as the distance between the chest wall and the point of maximal projection of the breast form. Values were calculated for final tissue expander expansion and at varying intervals 3, 6, and 12 months after implant placement. Results Fourteen breasts from 12 patients were included in the final analysis. Twelve of the 14 breasts had a loss of projection at three months following the implant placement or beyond. The percentage of projection lost in these 12 breasts ranged from 6.30% to 43.4%, with an average loss of projection of 21.05%. Conclusions This study is the first prospective quantitative analysis of temporal changes in breast projection after expander-implant reconstruction. By prospectively capturing projection data with three-dimensional photographic software, we reveal a loss of projection in this population by three months post-implant exchange. These findings will not only aid in managing patient expectations, but our methodology provides a foundation for future objective studies of the breast form

Waist-to-hip ratio is a better predictor than body mass index for morbidity in abdominally based breast reconstruction

BACKGROUND: Body mass index is a universally recognized measure of obesity. However, it does not take body fat distribution (BFD) into account, which has been established as a significant risk factor in both medicine and surgery. The objective of this study was to compare previously developed anthropometric measures of BFD with body mass index in predicting morbidity with abdominally based microsurgical breast reconstruction. METHODS: A review of patients who underwent abdominally based breast reconstruction was performed. Multivariate logistic regression was performed to determine the relationship between complications (recipient, donor, total) with body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio, conicity index, and abdominal volume index. RESULTS: A total of 325 patients who underwent 442 flaps were analyzed. Waist circumference (OR, 1.16; 95% CI 1.07-1.76), waist-to-hip ratio (OR, 1.94; 95% CI 1.25-3.35), and waist-to-height ratio (OR, 1.19; 95% CI 1.01-1.70) were significant risk factors for recipient site complications. Body mass index (OR, 1.14; 95% CI 1.01-1.56), and waist-to-hip ratio (OR, 2.01; 95% CI 1.30-3.95) were significant risk factors for donor site complications. Waist-to-hip ratio (OR, 1.87; 95% CI 1.22-4.00) was the only measure found to be a significant risk factor for experiencing any complication. A waist-to-hip ratio \u3e0.84 was associated with increased risk. CONCLUSIONS: Waist-to-hip ratio is a significant risk factor for recipient and donor site morbidity in abdominally based breast reconstruction. It is a readily calculable and clinically significant measure distinct from body mass index that should be considered for use in clinical care and research

The Relationship between Preoperative Wound Classification and Postoperative Infection: A Multi-Institutional Analysis of 15,289 Patients

BackgroundDespite advances in surgical techniques, sterile protocols, and perioperative antibiotic regimens, surgical site infections (SSIs) remain a significant problem. We investigated the relationship between wound classification (i.e., clean, clean/contaminated, contaminated, dirty) and SSI rates in plastic surgery.MethodsWe performed a retrospective review of a multi-institutional, surgical outcomes database for all patients undergoing plastic surgery procedures from 2006-2010. Patient demographics, wound classification, and 30-day outcomes were recorded and analyzed by multivariate logistic regression.ResultsA total of 15,289 plastic surgery cases were analyzed. The overall SSI rate was 3.00%, with superficial SSIs occurring at comparable rates across wound classes. There were similar rates of deep SSIs in the clean and clean/contaminated groups (0.64%), while rates reached over 2% in contaminated and dirty cases. Organ/space SSIs occurred in less than 1% of each wound classification. Contaminated and dirty cases were at an increased risk for deep SSIs (odds ratios, 2.81 and 2.74, respectively); however, wound classification did not appear to be a significant predictor of superficial or organ/space SSIs. Clean/contaminated, contaminated, and dirty cases were at increased risk for a postoperative complication, and contaminated and dirty cases also had higher odds of reoperation and 30-day mortality.ConclusionsAnalyzing a multi-center database, we found that wound classification was a significant predictor of overall complications, reoperation, and mortality, but not an adequate predictor of surgical site infections. When comparing infections for a given wound classification, plastic surgery had lower overall rates than the surgical population at large

A Biologically Active Surface Enzyme Assembly that Attenuates Thrombus Formation

Activation of hemostatic pathways by blood‐contacting materials remains a major hurdle in the development of clinically durable artificial organs and implantable devices. Here, it is postulated that surface‐induced thrombosis may be attenuated by the reconstitution onto blood contacting surfaces of bioactive enzymes that regulate the production of thrombin, a central mediator of both coagulation and platelet activation cascades. Thrombomodulin (TM), a transmembrane protein expressed by endothelial cells, is an established negative regulator of thrombin generation in the circulatory system. Traditional techniques to covalently immobilize enzymes on solid supports may modify residues contained within or near the catalytic site, thus reducing the bioactivity of surface enzyme assemblies. In this report, a molecular engineering and bioorthogonal chemistry approach to site‐specifically immobilize a biologically active recombinant human TM fragment onto the luminal surface of small diameter prosthetic vascular grafts is presented. Bioactivity and biostability of TM modified grafts is confirmed in vitro and the capacity of modified grafts to reduce platelet activation is demonstrated using a non‐human primate model. These studies indicate that molecularly engineered interfaces that display TM actively limit surface‐induced thrombus formation. A biologically active thrombomodulin surface assembly to limit interfacial thrombin production was generated on the lumen of clinical ePTFE vascular grafts by site‐specific covalent immobilization. Therapeutic capacity of this biomimetic surface engineering approach to attenuate thrombus formation was demonstrated in a clinically relevant in vivo model of prosthetic graft thrombosis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89494/1/4736_ftp.pd

Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women

BACKGROUND: A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. OBJECTIVE: The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). METHODS: We utilized a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualized, systems-based metric of clotting potential, termed the flow simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. RESULTS: Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly 3-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted OR 2.66; 95% CI 1.69–4.19; P<0.0001). CONCLUSIONS: A systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants

Combining Abdominal and Cosmetic Breast Surgery Does Not Increase Short-term Complication Rates: A Comparison of Each Individual Procedure and Pretreatment Risk Stratification Tool.

BACKGROUND: Combined abdominal and breast surgery presents a convenient and relatively cost-effective approach for accomplishing both procedures. OBJECTIVES: This study is the largest to date assessing the safety of combined procedures, and it aims to develop a simple pretreatment risk stratification method for patients who desire a combined procedure. METHODS: All women undergoing abdominoplasty, panniculectomy, augmentation mammaplasty, and/or mastopexy in the TOPS database were identified. Demographics and outcomes for combined procedures were compared to individual procedures using χ(2) and Student\u27s t-tests. Multiple logistic regression provided adjusted odds ratios for the effect of a combined procedure on 30-day complications. Among combined procedures, a logistic regression model determined point values for pretreatment risk factors including diabetes (1 point), age over 53 (1), obesity (2), and 3+ ASA status (3), creating a 7-point pretreatment risk stratification tool. RESULTS: A total of 58,756 cases met inclusion criteria. Complication rates among combined procedures (9.40%) were greater than those of aesthetic breast surgery (2.66%; P \u3c .001) but did not significantly differ from abdominal procedures (9.75%; P = .530). Nearly 77% of combined cases were classified as low-risk (0 points total) with a 9.78% complication rates. Medium-risk patients (1 to 3 points) had a 16.63% complication rate, and high-risk (4 to 7 points) 38.46%. CONCLUSIONS: Combining abdominal and breast procedures is safe in the majority of patients and does not increase 30-day complications rates. The risk stratification tool can continue to ensure favorable outcomes for patients who may desire a combined surgery. LEVEL OF EVIDENCE: 4 Risk