Matrix metalloproteinases in inflammatory bowel disease : expression, regulation and clinical relevance

Crohn__s disease (CD) is characterized by chronic, patchy, transmural inflammation of the entire gastrointestinal tract, while ulcerative colitis (UC) is manifested by chronic, continuous, superficial inflammation of the colon. Matrix metalloproteinases (MMPs) constitute a family of matrix degrading zinc and calcium-activated neutral endoproteinases, implicated in a wide range of biological processes. We found a marked upregulation of MMP-1, -2, -3 and -9 relative to their natural inhibitors, i.e., tissue inhibitors of metalloproteinases (TIMP) -1 and/or -2, in inflamed mucosa of IBD patients, paralleled by an increase in net MMP activity. Administration of TNF-alpha neutralizing antibody infliximab_ decreased MMP-1, -3 and -9 expression by cultured intestinal IBD explants and serum MMP-9 levels in CD patients, while MMP-2 levels remained almost the same. These observations suggest diverse regulator y pathways for the MMPs examined and a mechanistic pathway for infliximab_ in the treatment of CD. The T allele at TIMP-1 SNP locus +372 T/C, downregulating TIMP-1, appeared to enhance CD susceptibility and worsen prognosis of these patients. Ultimately, these studies might give rationale for the development of novel therapeutic drugs in IBD, based on the inhibition or activation of one or more members of the matrix metalloproteinases family.UBL - phd migration 201

Elastohydrodynamic film thickness and temperature measurements in dynamically loaded concentrated contacts : eccentric cam-flat follower

This paper describes some results of local film thickness and temperature measurements in an eccentric cam-flat follower contact by means of miniature vapour deposited thin layer transducers. Complex transducer patterns can be realized by employing photolithography, allowing local measurements in axial direction. A full film will develop at relatively low speeds. At high speeds chemical reaction layer formation starts. Film thickness and temperature at both sides of the contact differed appreciably, thus invalidating the assumption of line contact. Under high loads and misalignment a constriction in the film thickness, typically for EHD contacts, appears at the heavy load side. Only after supporting the follower on a self-aligning elastic hinge, a line contact condition could be attained. Temperature variations of the follower surface were found to be moderate. The transducers worked well and have a satisfying life expectancy

Modeling Personalized Adjuvant TreaTment in EaRly stage coloN cancer (PATTERN)

Aim: To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy. Methods: A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy. Results: Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively. Conclusion: This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): A multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

Elastohydrodynamic film thickness and temperature measurements in dynamically loaded concentrated contacts : eccentric cam-flat follower

This paper describes some results of local film thickness and temperature measurements in an eccentric cam-flat follower contact by means of miniature vapour deposited thin layer transducers. Complex transducer patterns can be realized by employing photolithography, allowing local measurements in axial direction. A full film will develop at relatively low speeds. At high speeds chemical reaction layer formation starts. Film thickness and temperature at both sides of the contact differed appreciably, thus invalidating the assumption of line contact. Under high loads and misalignment a constriction in the film thickness, typically for EHD contacts, appears at the heavy load side. Only after supporting the follower on a self-aligning elastic hinge, a line contact condition could be attained. Temperature variations of the follower surface were found to be moderate. The transducers worked well and have a satisfying life expectancy

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

Regulatieprocessen in de basale en klinische gastroenterologi