Challenges faced in developing an ideal chronic wound model

Introduction: Chronic wounds are a major drain on healthcare resources and can lead to substantial reductions in quality of life for those affected. Moreover, they often precede serious events such as limb amputations and premature death. In the long run, this burden is likely to escalate with an ageing population and lifestyle diseases such as obesity. Thus far, the identification of beneficial therapeutics against chronic wounds have been hindered by the lack of an ideal chronic wound animal model. Although animal models of delayed healing have been developed, none of these models fully recapitulate the complexity of the human chronic wound condition. Furthermore, most animals do not develop chronic wounds. Only the thoroughbred racehorse develops chronic ulcers. Areas covered: In this review, the different characteristics of chronic wounds that highlight its complexity are described. In addition, currently available models reflecting different aspects of chronic wound pathology and their relevance to human chronic wounds are discussed. This article concludes by listing relevant features representative of an ideal chronic wound model. Additionally, alternative approaches for the development of chronic wound models are discussed. Expert opinion: Delayed models of healing, including the streptozotocin diabetic model, skin flap model and magnet-induced IR models have emerged. While these models have been widely adopted for preclinical therapeutic testing, their relevance towards human chronic wounds remains debatable. In particular, current delayed healing models often fail to fully incorporate the key characteristics of chronic ulcers. Ultimately, more representative models are required to expedite the advancement of novel therapeutics to the clinic.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)Nanyang Technological UniversityPublished versionThis research is supported by the Agency for Science, Technology and Research (A*STAR) under its Industry Alignment Fund–Pre-Positioning Programme (IAF-PP) grant number H17/01/a0/0C9 as part of the Wound Care Innovation for the Tropics (WCIT) Programme. This research is also supported by the Agency for Science, Technology and Research (A*STAR) under its Industry Alignment Fund–Pre-Positioning Programme (IAF-PP) grant number H1701a0004 and the Skin Research Institute of Singapore, Phase 2: SRIS@Novena. Nanyang Technological University (Start-up grant) and the Ministry of Education (Tier 1 T1-002-098 and T1-002-013) also supported this research

Advanced Omics and Radiobiological Tissue Archives: The Future in the Past

Archival formalin-fixed, paraffin-embedded (FFPE) tissues and their related diagnostic records are an invaluable source of biological information. The archival samples can be used for retrospective investigation of molecular fingerprints and biomarkers of diseases and susceptibility. Radiobiological archives were set up not only following clinical performance such as cancer diagnosis and therapy but also after accidental and occupational radiation exposure events where autopsies or cancer biopsies were sampled. These biobanks provide unique and often irreplaceable materials for the understanding of molecular mechanisms underlying radiation-related biological effects. In recent years, the application of rapidly evolving “omics” platforms, including transcriptomics, genomics, proteomics, metabolomics and sequencing, to FFPE tissues has gained increasing interest as an alternative to fresh/frozen tissue. However, omics profiling of FFPE samples remains a challenge mainly due to the condition and duration of tissue fixation and storage, and the extraction methods of biomolecules. Although biobanking has a long history in radiation research, the application of omics to profile FFPE samples available in radiobiological archives is still young. Application of the advanced omics technologies on archival materials provides a new opportunity to understand and quantify the biological effects of radiation exposure. These newly generated omics data can be well integrated into results obtained from earlier experimental and epidemiological analyses to shape a powerful strategy for modelling and evaluating radiation effects on health outcomes. This review aims to give an overview of the unique properties of radiation biobanks and their potential impact on radiation biology studies. Studies recently performed on FFPE samples from radiobiology archives using advanced omics are summarized. Furthermore, the compatibility of archived FFPE tissues for omics analysis and the major challenges that lie ahead are discussed

Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities

Summary: The transcriptional co-activator YAP forms complexes with distinct transcription factors, controlling cell fate decisions, such as proliferation and apoptosis. However, the mechanisms underlying its context-dependent function are poorly defined. This study explores the interplay between the TGF-β and Hippo pathways and their influence on YAP’s association with specific transcription factors. By integrating iterative mathematical modeling with experimental validation, we uncover molecular switches, predominantly controlled by RASSF1A and ITCH, which dictate the formation of YAP-SMAD (proliferative) and YAP-p73 (apoptotic) complexes. Our results show that RASSF1A enhances the formation of apoptotic complexes, whereas ITCH promotes the formation of proliferative complexes. Notably, higher levels of ITCH transform YAP-SMAD activity from a transient to a sustained state, impacting cellular behaviors. Extending these findings to various breast cancer cell lines highlights the role of cellular context in YAP regulation. Our study provides new insights into the mechanisms of YAP transcriptional activities and their therapeutic implications

The STORE platform for data and resource sharing in radiation biology, radioecology and epidemiology

The primary data produced in the course of publicly-funded science represents a common asset for society as much as the analysed and interpreted results. Recent years have seen widespread agreement that such data should be accessible by scientists and the public. Open access publication has been the focus of much attention. However, the public availability of primary data requires the establishment of governance and a sharing infrastructure. International guidelines have been established for open data (FAIR) and transparent publication (TOP). Availability and reuse of primary scientific data increases the accountability, reproducibility and value of publicly funded science and assures that research resources developed with public funds become readily available to the broader research community ultimately to the benefit of the public. Furthermore, journals and funders are increasingly requiring that all study data are made openly available. In response to these needs, in radiation protection research we have developed the STORE data sharing platform, initially funded under the European Commission’s EURATOM programme. STORE permits users to upload and share data; users can maintain control over data dissemination through Creative Commons licensing. The data structure in STORE is centred on the study which is a top level directory. Within a study there are datasets and within these there can be individual files or data elements, which can be of any type or size and annotated with standard metadata Each dataset and data item are assigned a STORE ID and a DOI. STORE currently contains about 100 studies and more than 3000 individual data elements, which range from epidemiology data, through images to proteomics and raw mass spectroscopy data. STORE is compliant with the FAIR data principles and is registered with r3Data, the ELIXIR/EBI-based MIRIAM register of persistent identifiers, and the FAIR sharing initiative. STORE (http://www.storedb.org) is open and free to investigators and to funding agencies as a central repository for data sharing

Evaluation of the Trophic Structure of the West Florida Shelf in the 2000s Using the Ecosystem Model OSMOSE

We applied the individual-based, multi-species OSMOSE modeling approach to the West Florida Shelf, with the intent to inform ecosystem-based management (EBM) in this region. Our model, referred to as ‘OSMOSE-WFS’, explicitly considers both pelagic-demersal and benthic high trophic level (HTL) groups of fish and invertebrate species, and is forced by the biomass of low trophic level groups of species (plankton and benthos). We present a steady-state version of the OSMOSE-WFS model describing trophic interactions in the West Florida Shelf in the 2000s. OSMOSE-WFS was calibrated using a recently developed evolutionary algorithm that allowed simulated biomasses of HTL groups to match observed biomasses over the period 2005–2009. The validity of OSMOSE-WFS was then evaluated by comparing simulated diets to observed ones, and the simulated trophic levels to those in an Ecopath model of the West Florida Shelf (WFS Reef fish Ecopath). Finally, OSMOSE-WFS was used to explore the trophic structure of the West Florida Shelf in the 2000s and estimate size-specific natural mortality rates for a socio-economically important species, gag grouper (Mycteroperca microlepis). OSMOSE-WFS outputs were in full agreement with observations as to the body size and ecological niche of prey of the different HTL groups, and to a lesser extent in agreement with the observed species composition of the diet of HTL groups. OSMOSE-WFS and WFS Reef fish Ecopath concurred on the magnitude of the instantaneous natural mortality of the different life stages of gag grouper over the period 2005–2009, but not always on the main causes of natural mortality. The model evaluations conducted here provides a strong basis for ongoing work exploring fishing and environmental scenarios so as to inform EBM. From simple size-based predation rules, we were indeed able to capture the complexity of trophic interactions in the West Florida Shelf, and to identify the predators, prey and competitors of socio-economically important species as well as pivotal prey species of the ecosystem

WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway

Abnormal activation the WNT/β-catenin signaling pathway has been associated with ovarian carcinomas, but a specific WNT ligand and pertinent downstream mechanisms are not fully understood. In this study, we found abundant WNT7A in the epithelium of serous ovarian carcinomas, but not detected in borderline and benign tumors, normal ovary or endometrioid carcinomas. To characterize the role of WNT7A in ovarian tumor growth and progression, nude mice were injected either intraperitoneally (i.p.) or subcutaneously (s.c.) with WNT7A knocked down SKOV3.ip1 and overexpressed SKOV3 cells. In the i.p. group, mice receiving SKOV3.ip1 cells with reduced WNT7A expression developed significantly fewer tumor lesions. Gross and histological examination revealed greatly reduced invasion of WNT7A knockdown cells into intestinal mesentery and serosa compared to the control cells. Tumor growth was regulated by loss or overexpression of WNT7A in mice receiving s.c. injection as well. In vitro analysis of cell function revealed that cell proliferation, adhesion, and invasion were regulated by WNT7A. The activity of the TCF/LEF reporter was stimulated by overexpression of WNT7A in ovarian cancer cells. Co-transfection with WNT7A and FZD5 receptor further increased activity, and this effect was inhibited by co-transfection with SFRP2, or dominant-negative TCF4. Overexpression of WNT7A stimulated MMP7 promoter, and mutation of TCF binding sites in MMP7 promoter confirmed that activation of MMP7 promoter by WNT7A was mediated by β-catenin/TCF signaling. Collectively, these results suggest that re-expression of WNT7A during malignant transformation of ovarian epithelial cells plays a critical role in ovarian cancer progression mediated by WNT/β-catenin signaling pathway