Constitutive Activation of BMP Signalling Abrogates Experimental Metastasis of OVCA429 Cells via Reduced Cell Adhesion

BACKGROUND: Activation of bone morphogenetic protein (BMP)4 signalling in human ovarian cancer cells induces a number of phenotypic changes in vitro, including altered cell morphology, adhesion, motility and invasion, relative to normal human ovarian surface epithelial cells. From these in vitro analyses, we had hypothesized that active BMP signalling promotes the metastatic potential of ovarian cancer. METHODS: To test this directly, we engineered OVCA429 human ovarian cancer cells possessing doxycycline-inducible expression of a constitutively-active mutant BMP receptor, ALK3QD, and administered these cells to immunocompromised mice. Further characterization was performed in vitro to address the role of activated BMP signalling on the EOC phenotype, with particular emphasis on epithelial-mesenchymal transition (EMT) and cell adhesion. RESULTS: Unexpectedly, doxycycline-induced ALK3QD expression in OVCA429 cells reduced tumour implantation on peritoneal surfaces and ascites formation when xenografted into immunocompromised mice by intraperitoneal injection. To determine the potential mechanisms controlling this in vivo observation, we followed with several cell culture experiments. Doxycycline-induced ALK3QD expression enhanced the refractile, spindle-shaped morphology of cultured OVCA429 cells eliciting an EMT-like response. Using in vitro wound healing assays, we observed that ALK3QD-expressing cells migrated with long, cytoplasmic projections extending into the wound space. The phenotypic alterations of ALK3QD-expressing cells correlated with changes in specific gene expression patterns of EMT, including increased Snail and Slug and reduced E-cadherin mRNA expression. In addition, ALK3QD signalling reduced beta1- and beta3-integrin expression, critical molecules involved in ovarian cancer cell adhesion. The combination of reduced E-cadherin and beta-integrin expression correlates directly with the reduced EOC cell cohesion in spheroids and reduced cell adhesion to the extracellular matrix substrates fibronectin and vitronectin that was observed. CONCLUSIONS: We propose that the key steps of ovarian cancer metastasis, specifically cell cohesion of multicellular aggregates in ascites and cell adhesion for reattachment to secondary sites, may be inhibited by overactive BMP signalling, thereby decreasing the ultimate malignant potential of ovarian cancer in this model system

Disruptive technologies in health care disenchanted: A systematic review of concepts and examples

Objectives To clarify the concept of disruptive technologies in health care, provide examples and consider implications of potentially disruptive technologies for health technology assessment (HTA). Methods We conducted a systematic review of conceptual and empirical papers on healthcare technologies that are described as disruptive. We searched MEDLINE and Embase from 2013 to April 2019 (updated in December 2021). Data extraction was done in duplicate by pairs of reviewers utilizing a data extraction form. A qualitative data analysis was undertaken based on an analytic framework for analysis of the concept and examples. Key arguments and a number of potential predictors of disruptive technologies were derived and implications for HTA organizations were discussed. Results Of 4,107 records, 28 were included in the review. Most of the papers included conceptual discussions and business models for disruptive technologies; only few papers presented empirical evidence. The majority of the evidence is related to the US healthcare system. Key arguments for describing a technology as disruptive include improvement of outcomes for patients, improved access to health care, reduction of costs and better affordability, shift in responsibilities between providers, and change in the organization of health care. A number of possible predictors for disruption were identified to distinguish these from sustaining innovations. Conclusions Since truly disruptive technologies could radically change technology uptake and may modify provision of care patterns or treatment paths, they require a thorough evaluation of the consequences of using these technologies, including economic and organizational impact assessment and careful monitoring.Fil: Perleth, Matthias. Gemeinsamer Bundesausschuss; AlemaniaFil: Di Bidino, Rossella. Fondazione Policlinico Universitario Agostino Gemelli Irccs; ItaliaFil: Huang, Li Ying. Center For Drug Evaluation; ChinaFil: Jones, Lydia. Gemeinsamer Bundesausschuss; AlemaniaFil: Mujoomdar, Michelle. Canadian Agency For Drugs And Technologies In Health; CanadáFil: Myles, Susan. Health Technology Wales; Reino UnidoFil: Pichón-riviere, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Sabirin, Junainah. Ministry of Health Malaysi; MalasiaFil: Schuller, Tara. International Network of Agencies for Health Technology Assessment; CanadáFil: Washington, Jennifer. Health Technology Wales; Reino Unid

Bringing regenerative medicines to the clinic: the future for regulation and reimbursement.

Significant investments in regenerative medicine necessitate discussion to align evidentiary requirements and decision-making considerations from regulatory, health system payer and developer perspectives. Only with coordinated efforts will the potential of regenerative medicine be realized. We report on discussions from two workshops sponsored by NICE, University of Alberta, Cell Therapy Catapult and Centre for Commercialization of Regenerative Medicine. We discuss methods to support the assessment of value for regenerative medicine products and services and the synergies that exist between market authorization and reimbursement regulations and practices. We discuss the convergence in novel adaptive licensing practices that may promote the development and adoption of novel therapeutics that meet the needs of healthcare payers. </jats:p

Challenges of health technology assessment in pluralistic healthcare systems: an ISPOR council report

Health technology assessment (HTA) has been growing in use over the past 40 years, especially in its impact on decisions regarding the reimbursement, adoption, and use of new drugs, devices, and procedures. In countries or jurisdictions with “pluralistic” healthcare systems, there are multiple payers or sectors, each of which could potentially benefit from HTA. Nevertheless, a single HTA, conducted centrally, may not meet the needs of these different actors, who may have different budgets, current standards of care, populations to serve, or decision-making processes. This article reports on the research conducted by an ISPOR Health Technology Assessment Council Working Group established to examine the specific challenges of conducting and using HTA in countries with pluralistic healthcare systems. The Group used its own knowledge and expertise, supplemented by a narrative literature review and survey of US payers, to identify existing challenges and any initiatives taken to address them. We recommend that countries with pluralistic healthcare systems establish a national focus for HTA, develop a uniform set of HTA methods guidelines, ensure that HTAs are produced in a timely fashion, facilitate the use of HTA in the local setting, and develop a framework to encourage transparency in HTA. These efforts can be enhanced by the development of good practice guidance from ISPOR or similar groups and increased training to facilitate local use of HTA