Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis

SIMPLE SUMMARY: MMP-13 is an enzyme that can digest and disrupt the tissue structures surrounding epithelial cells that line the surface of many internal organs, as well as the tissue structures surrounding endothelial cells that line the surface of blood vessels. The production of MMP-13 is tightly controlled in physiological conditions but is increased in various cancers and plays multiple roles in tumour progression and metastasis. This review summarises the current understanding of the regulation of MMP-13 production and discusses the actions of MMP-13 in cancer progression and metastasis. ABSTRACT: Matrix metalloproteinase-13 (MMP-13) is a member of the Matrix metalloproteinases (MMPs) family of endopeptidases. MMP-13 is produced in low amounts and is well-regulated during normal physiological conditions. Its expression and secretion are, however, increased in various cancers, where it plays multiple roles in tumour progression and metastasis. As an interstitial collagenase, MMP-13 can proteolytically cleave not only collagens I, II and III, but also a range of extracellular matrix proteins (ECMs). Its action causes ECM remodelling and often leads to the release of various sequestered growth and angiogenetic factors that promote tumour cell growth, invasion and angiogenesis. This review summarizes our current understanding of the regulation of MMP-13 expression and secretion and discusses the actions of MMP-13 in cancer progression and metastasis

A new model for in vitro testing of vitreous substitute candidates

Purpose: To describe a new model for in vitro assessment of novel vitreous substitute candidates. Methods: The biological impact of three vitreous substitute candidates was explored in a retinal explant culture model; a polyalkylimide hydrogel (Bio-Alcamid®), a two component hydrogel of 20 wt.% poly (ethylene glycol) in phosphate buffered saline (PEG) and a cross-linked sodium hyaluronic acid hydrogel (Healaflow®). The gels where applied to explanted adult rat retinas and then kept in culture for 2, 5 and 10 days. Gel-exposed explants were compared with explants incubated under standard tissue culture conditions. Cryosections of the specimens were stained with hematoxylin and eosin, immunohistochemical markers (GFAP, Vimentin, Neurofilament 160, PKC, Rhodopsin) and TUNEL. Results: Explants kept under standard conditions as well as PEG-exposed explants displayed disruption of retinal layers with moderate pyknosis of all neurons. They also displayed moderate labeling of apoptotic cells. Bio-Alcamid®-exposed explants displayed severe thinning and disruption of retinal layers with massive cell death. Healaflow®-treated explants displayed normal retinal lamination with significantly better preservation of retinal neurons compared with control specimens, and almost no signs of apoptosis. Retinas exposed to Healaflow® and retinas kept under standard conditions showed variable labeling of GFAP with generally low expression and some areas of upregulation. PEG-exposed retinas showed increased GFAP labeling and Bio-Alcamid®-exposed retinas showed sparse labeling of GFAP. Conclusions Research into novel vitreous substitutes has important implications for both medical and surgical vitreoretinal disease. The in vitro model presented here provides a method of biocompatibility testing prior to more costly and cumbersome in vivo experiments. The explant culture system imposes reactions within the retina including disruption of layers, cell death and gliosis, and the progression of these reactions can be used for comparison of vitreous substitute candidates. Bio-Alcamid® had strong adverse effects on the retina which is consistent with results of prior in vivo trials. PEG gel elicits reactions similar to the control retinas whereas Healaflow® shows protection from culture-induced trauma indicating favorable biocompatibility.Swedish Research CouncilUniversity of Lund. Medical FacultyPrincess Margaret's Foundation for Blind ChildrenKnut and Alice Wallenberg FoundationGeneral Sir John Monash Foundation (Scholarship)In Vivo Therapeutics Corporatio

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of rectal cancer

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of small rectal cancer Objective For patients with early rectal cancer, who are either at high risk for or refuse surgery, a planned organ preservation treatment involving a combination of external beam radiotherapy (EBRT) and Contact X-ray Brachytherapy (CXB) can be offered as an alternative option to surgery. (1-3) However, the ideal sequence of treatment for small rectal tumours (≤3cm), whether to administer CXB first or after EBRT, has not yet been well established, leading to variable sequences of this organ-preserving treatment being used.(3-5) This study has compared the oncological outcomes between the two treatment approaches using propensity score matching and inverse probability treatment weighting (IPTW) analysis to evaluate whether starting with CXB confers any benefits to patients. Method We analysed patients who had undergone both EBRT and CXB with curative intent, regardless of the treatment sequence, from the prospectively collected database at Clatterbridge Cancer Centre (2008-2019). Only patients who had well to moderately differentiated rectal adenocarcinoma (cT1-3, cN0-1, cM0) and small tumour size (≤ 3cm) were included. The variables of age, sex, fitness for surgery, performance status, tumour stage, nodal stage, EBRT regimen and CXB total dose, were considered possible confounders of the association between treatment regimen and outcomes. The balance of covariates before and after propensity matching and IPTW was assessed by examining the standardised mean difference (SMD) between the groups (Figure 1). The oncological outcomes based on the treatment sequence were first assessed in an unadjusted analysis followed by an adjusted model analysis considering all variables as confounders. Then, we performed propensity score matching (nearest-neighbour method, calliper= 0.25) and calculated IPTW to weigh the full cohort in each regression model. Statistical analysis was performed in R 4.3.1. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Secondary outcome measures consisted of the local regrowth rate, organ preservation rate, and presence of post-treatment rectal bleeding. Results A total of 251 eligible patients, who received either EBRT (n=103) or CXB (n=148) as their initial treatment with curative intent were included in the study. Patients received a CXB dose of 90-110Gy in 3-4 fractions over 4-6 weeks (each fraction two weeks apart) either before or after EBRT. EBRT was administered either as long-course chemoradiotherapy (45-50Gy/25 #/35 days), long-course radiotherapy alone (45Gy/20#/28days), or short-course radiotherapy (25Gy/5#/5 days). Following treatment, a watch-and-wait policy was adopted for patients who achieved a clinical complete/near response. The median follow-up was 37 [IQR:18-56] months for the EBRT-first group and 32 [IQR:16-54] months for the CXB-first group. In the unadjusted analysis, a higher risk of grade-1(26%) and grade-2(6%) rectal bleeding (p=0.008) was observed in patients who started with CXB, but no significant differences in any of the survival parameters were found. Analysis using the adjusted, propensity matching, and IPTW models, demonstrated a significant improvement of OS (p=0.04, HR (95%CI): 0.69 (0.48-0.98) and a higher risk of grade 1-2 rectal bleeding (p=0.01, OR (95%CI): 2.35(1.16-4.76) in those patients who had been received CXB as their initial treatment (Figure 2). However, DFS (p=0.87), local regrowth rate (p=0.70), and organ preservation rate (p=0.80) were not significantly different between the two groups. Conclusion Small rectal cancer (≤3cm), commencing treatment with CXB, as opposed to EBRT, was associated with improved overall survival, despite an increased risk of grade 1 and 2 rectal bleeding. However, there was no statistically significant improvement in terms of disease-free survival, local regrowth rate, or organ preservation rate with this treatment strategy

Clinical prediction models assessing response to radiotherapy for rectal cancer: protocol for a systematic review.

BackgroundRectal cancer has a high prevalence. The standard of care for management of localised disease involves major surgery and/or chemoradiotherapy, but these modalities are sometimes associated with mortality and morbidity. The notion of 'watch and wait' has therefore emerged and offers an organ-sparing approach to patients after administering a less invasive initial treatment, such as X-ray brachytherapy (Papillon technique). It is thus important to evaluate how likely patients are to respond to such therapies, to develop patient-tailored treatment pathways. We propose a systematic review to identify published clinical prediction models of the response of rectal cancer to treatment that includes radiotherapy and here present our protocol.MethodsIncluded studies will develop multivariable clinical prediction models which assess response to treatment and overall survival of adult patients who have been diagnosed with any stage of rectal cancer and have received radiotherapy treatment with curative intent. Cohort studies and randomised controlled trials will be included. The primary outcome will be the occurrence of salvage surgery at 1 year after treatment. Secondary outcomes include salavage surgery at at any reported time point, the predictive accuracy of models, the quality of the developed models and the feasibility of using the model in clinical practice. Ovid MEDLINE, PubMed, Cochrane Library, EMBASE and CINAHL will be searched from inception to 24 February 2022. Keywords and phrases related to rectal cancer, radiotherapy and prediction models will be used. Studies will be selected once the deduplication, title, abstract and full-text screening process have been completed by two independent reviewers. The PRISMA-P checklist will be followed. A third reviewer will resolve any disagreement. The data extraction form will be pilot-tested using a representative 5% sample of the studies reviewed. The CHARMS checklist will be implemented. Risk of bias in each study will be assessed using the PROBAST tool. A narrative synthesis will be performed and if sufficient data are identified, meta-analysis will be undertaken as described in Debray et al. DISCUSSION: This systematic review will identify factors that predict response to the treatment protocol. Any gaps for potential development of new clinical prediction models will be highlighted.Trial registrationCRD42022277704

Landscape of stimulation-responsive chromatin across diverse human immune cells.

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells

Radio Variable and Transient Sources on Minute Timescales in the ASKAP Pilot Surveys

We present results from a radio survey for variable and transient sources on 15-min timescales, using the Australian SKA Pathfinder (ASKAP) pilot surveys. The pilot surveys consist of 505 h of observations conducted at around 1 GHz observing frequency, with a total sky coverage of 1476 deg$^2$. Each observation was tracked for approximately 8-10h, with a typical rms sensitivity of $\sim$30 $\mu$jy/beam and an angular resolution of $\sim$12 arcsec. The variability search was conducted within each 8-10h observation on a 15-min timescale. We detected 38 variable and transient sources. Seven of them are known pulsars, including an eclipsing millisecond pulsar, PSR J2039$-$5617. Another eight sources are stars, only one of which has been previously identified as a radio star. For the remaining 23 objects, 22 are associated with active galactic nuclei or galaxies (including the five intra-hour variables that have been reported previously), and their variations are caused by discrete, local plasma screens. The remaining source has no multi-wavelength counterparts and is therefore yet to be identified. This is the first large-scale radio survey for variables and transient sources on minute timescales at a sub-mJy sensitivity level. We expect to discover $\sim$1 highly variable source per day using the same technique on the full ASKAP surveys.Comment: 20 pages, 11 figures; accepted for publication in MNRA