The role of Matrix Metalloproteinase-8 in anti-cancer immunity

The existing literature suggests that MMP-8 is protective in the context of several cancers. In breast cancer (BC) patients, MMP-8 expression correlates with increased relapse free survival. In vivo,absence of Mmp8 increases tumour burden and lung metastasis in the MMTV-PyMT spontaneous mouse mammary cancer model. Data imply that the putative host-protective role of MMP-8 may be via its ability to orchestrate the immune system. Therefore, in vivo studies were required to establish the mechanistic link between MMP-8 and immunity. Using Mmp8 null mice orthotopically injected with MMTV-PyMT-derived mammary tumours, we have found conflicting data in this alternative model. There was no impact on tumour volume in the absence of Mmp8 and there were no consistent changes to intra-tumoural immune infiltrates by flow cytometry or cytokine gene expression in comparison to wild-type controls. As a caveat to these findings, upon sequencing of the Casp11 gene in Mmp8 nullmice, a 5 base-pair deletion was discovered, rendering caspase-11 non-functional. This finding prevented definitive conclusions to be made on the impact of MMP-8 in our existing mice, therefore investigations were carried out to ascertain whether the passenger mutation contributed to any results by using the Mmp8 KO mouse without the Casp11 mutation. However, using these animals there was still a lack of tumour or immune phenotype. This leads to two conclusions: firstly, our data suggests that the passenger mutation did not contribute to any phenotype or lack thereof. Moreover, MMP-8 did not suppress primary growth of orthotopically implanted BC tumours via co-ordination of the immune system. The discrepancy with previous findings advocates for further exploration of the differences between the spontaneous and orthotopic implant model in Mmp8 KO mice to pinpoint the role of MMP-8 in tumourigenesis

ADAMTS-1 and Syndecan-4 intersect in the regulation of cell migration and angiogenesis

ADAMTS-1 is an extracellular protease with critical roles in organogenesis and angiogenesis. Here we demonstrate a functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration and angiogenesis. Knockdown of ADAMTS-1 in endothelial cells resulted in a parallel reduction in cell surface syndecan-4, attributable to increased matrix metalloproteinase-9 (MMP9) activity. Knockdown of either ADAMTS-1 or syndecan-4 increased cellular responses to vascular endothelial growth factor A isoform VEGFA164, and increased ex vivo aortic ring microvessel sprouting. On fibronectin, knockdown of either protein enhanced migration and promoted formation of long α5 integrin-containing fibrillar adhesions. However, integrin α5 null cells still showed increased migration in response to ADAMTS-1 and syndecan-4 siRNA treatment. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1 and syndecan-4 knockdown cells demonstrated that the altered adhesive behaviour was matrix dependent, and this correlated with a lack of expression of fibulin-1: an extracellular matrix co-factor for ADAMTS-1 that is known to inhibit migration. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via collaboration with MMP9 and fibulin-1.This article has an associated First Person interview with the first author of the paper

Percutaneous cervical cordotomy for cancer-related pain : national data

Objectives: Percutaneous cervical cordotomy (PCC) is an interventional ablative procedure in the armamentarium for cancer pain treatment, but there is limited evidence to support its use. This study aimed to assess the effectiveness and safety of PCC. Methods: Analysis was undertaken of the first national (UK) prospective data repository of adult patients with cancer undergoing PCC for pain treatment. The relationship between pain and other outcomes before and after PCC was examined using appropriate statistical methods. Results: Data on 159 patients’ PCCs (performed from 1 January 2012 to 6 June 2017 in three centres) were assessed: median (IQR) age was 66 (58–71) years, 47 (30%) were female. Mesothelioma was the most common primary malignancy (57%). The median (IQR) time from cancer diagnosis to PCC assessment was 13.3 (6.2–23.2) months; PCC to follow-up was 9 (8–25) days; and survival after PCC was 1.3 (0.6–2.8) months. The mean (SD) for ‘average pain’ using a numerical rating scale was 6 (2) before PCC and 2 (2) at follow-up, and for ‘worst pain’ 9 (1) and 3 (3), respectively. The median (IQR) reduction in strong opioid dose at follow-up was 50% (34–50). With the exception of ‘activity’, all health-related quality of life scores (5-level version of EuroQol-5 Dimension) either improved or were stable after PCC. Six patients (4%) had PCC-related adverse events. Conclusions: PCC is an effective treatment for cancer pain; however, findings in this study suggest PCC referrals tended to be late in patients’ disease trajectories. Further study into earlier treatment and seeking international consensus on PCC outcomes will further enhance opportunities to improve patient care

Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth

The gut microbiota's function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria, Faecalibaculum rodentium, rescued this increased tumor growth. Single-cell transcriptomics identified an increased number of cells with a stromal signature in tumors, and subsequent histology revealed an increased abundance of mast cells in the tumor stromal regions. We show that administration of a mast cell stabilizer, cromolyn, rescues increased tumor growth in antibiotic treated animals but has no influence on tumors from control cohorts. These findings highlight that BrCa-microbiota interactions are different from other cancers studied to date and suggest new research avenues for therapy development

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

A comparison of the effectiveness of 'semantic' and 'phonological' tasks in the facilitation of word production in aphasia

In the treatment of word finding in anomia both 'phonological' tasks (e.g. repetition, phonemic cueing), and 'semantic' tasks (e.g. word-picture matching, semantic judgements) have been found to be effective. However, there have been few direct comparisons of the relative effectiveness of these tasks within the same individuals: most reports differ in both tasks and participants. Hence it is difficult to distinguish whether differences in task efficacy are due to differences in the impairments of the people with aphasia treated, or subtle differences within the tasks. Hence, here we examine the efficacy of 'semantic' tasks (semantic judgement questions) and 'phonological' tasks (repetition, phonemic cueing) in facilitation with a case series of people with aphasia, and address the question: Do semantic and phonological tasks differ in their efficacy within and across individuals

The facilitation of word production in Aphasia : what can it do for the clinician?

Finding the best approach to remedy the word finding problems that people with aphasia often have has been a vexed question. The last 30 years has seen the emergence of investigations using facilitation, the once only application of a treatment, as a tool, within a cognitive neuropsychology framework. Here, we provide an overview of some major contributions to this growing body of evidence and a discussion on applying it in clinical practice. We introduce readers to a current project that seeks to answer some important questions that have emerged over the years. These questions include whether the effects of facilitation are robust over time, whether different types of facilitation tasks differ in effectiveness, the relationship between level of impairment and type of facilitation and, whether facilitation can help choose the best treatment for this often-intractable problem.3 page(s

Can assessment predict facilitation outcomes for people with word-finding difficulties?

It has been hypothesised that different word-finding impairments in people with aphasia, will be best remediated by different treatments (e.g., Hillis & Caramazza, 1994). To date, however, no clear or predictable relationship has emerged between the type of word-finding problem and the most appropriate treatment task (Best & Nickels, 2000). As therapy is a time consuming and costly process, it is clearly desirable for both the client and the clinician to be able to match the nature of the word-finding problem to the most appropriate treatment, as quickly as possible. This paper reports preliminary results from the first phase of a larger project, which aims to identify whether the response to using a task once, “facilitation”, can predict the response to the same task used repeatedly over time, “therapy”. The first phase, reported here examines the effects of two different tasks used once in a facilitation paradigm on subsequent picture naming of people with aphasia. This project aims to address three questions: • Do tasks that focus on word meaning (semantics) and those focusing on word sound (phonology) produce equal facilitation effects or do they vary in efficacy across and/or within individuals? • Do individuals with different levels of impairment in spoken word production (e.g., semantic or phonological) respond differently to facilitation? • Is there an interaction between 1 & 2 (i.e., are some tasks more effective than others for individuals with a particular level of impairment)? To date, five individuals have been tested. Only one individual showed a significant benefit from a facilitation task, on subsequent picture naming at least 10 minutes later. This individual, benefited from phonological facilitation (repetition in the presence of a picture) but failed to benefit from semantic facilitation (feature verification, e.g., Does it bark?). No other individual showed any benefit from the facilitation tasks. Why have the results of facilitation been so limited? For phonological facilitation it is possible that retesting happens too late: some previous studies have found that there were only short term benefits from facilitation, with no lasting effects observable 10 minutes later (the time at which we retest). For semantic facilitation it is possible that the fact we do not include the phonological form of the word in the question influences efficacy: LeDorze et al. (1994) found facilitation effects from a semantic task ONLY when the phonological form was provided. Further investigation is currently underway, to test these hypotheses, with the individuals tested to date, and additional aphasic participants.2 page(s

Can the effects of facilitation predict the effects of treatment?

In the treatment of word-finding in anomia, there has been no simple correspondence between the treatment used, the impairment and the success of the treatment. For the clinician, therapy remains something of a ‘lucky dip’. Even with the best assessment and a theoretically guided choice of treatment, there is no guarantee of success. In this project we investigate whether it is possible, by using a task once (facilitation) to predict whether the same task will be successful as treatment. Participants were first given a series of tasks (e.g. semantic feature questions; repetition) and the effects of one application of these tasks on their subsequent naming was examined. Subsequently, for each individual, one task that was successful and one that was not was chosen and used repeatedly as treatment. We will discuss the relationship between the results of facilitation and the results of treatment and the implications for clinical practice.5 page(s