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Hyaluronan is a simple repeating disaccharide polymer, synthesized at the cell surface by integral membrane synthases. The repeating sequence is perfectly homogeneous, and is the same in all vertebrate tissues and fluids. The polymer molecular mass is more variable. Most commonly, hyaluronan is synthesized as a high-molecular mass polymer, with an average molecular mass of approximately 1000-8000 kDa. There are a number of studies showing increased hyaluronan content, but reduced average molecular mass with a broader range of sizes present, in tissues or fluids when inflammatory or tissue-remodeling processes occur. In parallel studies, exogenous hyaluronan fragments of low-molecular mass (generally, <200 kDa) have been shown to affect cell behavior through binding to receptor proteins such as CD44 and RHAMM (gene name HMMR), and to signal either directly or indirectly through toll-like receptors. These data suggest that receptor sensitivity to hyaluronan size provides a biosensor of the state of the microenvironment surrounding the cell. Sensitive methods for isolation and characterization of hyaluronan and its fragments have been developed and continue to improve. This review provides an overview of the methods and our current state of knowledge of hyaluronan content and size distribution in biological fluids and tissues.

This review summarizes the roles of CAFs in forming a \"cancerized\" fibrotic stroma favorable to tumor initiation and dissemination, in particular highlighting the functions of the extracellular matrix component hyaluronan (HA) in these processes. The structural complexity of the tumor and its host microenvironment is now well appreciated to be an important contributing factor to malignant progression and resistance-to-therapy. There are multiple components of this complexity, which include an extensive remodeling of the extracellular matrix (ECM) and associated biomechanical changes in tumor stroma. Tumor stroma is often fibrotic and rich in fibrillar type I collagen and hyaluronan (HA). Cancer-associated fibroblasts (CAFs) are a major source of this fibrotic ECM. CAFs organize collagen fibrils and these biomechanical alterations provide highways for invading carcinoma cells either under the guidance of CAFs or following their epithelial to mesenchymal transition (EMT). The increased HA metabolism of a tumor microenvironment instructs carcinoma initiation and dissemination by performing multiple functions. The key effects of HA reviewed here are its role in activating CAFs in pre-malignant and malignant stroma, and facilitating invasion by promoting motility of both CAFs and tumor cells, thus facilitating their invasion. Circulating CAFs (cCAFs) also form heterotypic clusters with circulating tumor cells (CTC), which are considered to be pre-cursors of metastatic colonies. cCAFs are likely required for extravasation of tumors cells and to form a metastatic niche suitable for new tumor colony growth. Therapeutic interventions designed to target both HA and CAFs in order to limit tumor spread and increase response to current therapies are discussed.

Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to “cancerization” of the tumor microenvironment.

IntroductionPeople with severe mental illness have an increased vulnerability to cardiovascular disease due to multilple biopsychosocial factors and a potential adverse effects of longer term treatment with anti-psychotic medications. Treatment of severe and enduring mental illness with antipsychotic medications is likely to cause metabolic changes leading to weight gain and dyslipidaemia, thus increasing risk of cardiovascular disease. Cardiometabolic risk screening can be done using Lester Tool which also provides recommendations for interventions.ObjectivesTo identify the compliance to Lester Tool in the monitoring of cardiometabolic risk factors and intervention provided on acute psychiatry inpatients.MethodsWe carried out a retrospective audit of 30 patients on regular antipsychotic medication on an adult inpatient ward in Macclesfield, United Kingdom. Electronic records were reviewed to establish whether the smoking status, lifestyle, BMI, blood pressure, blood glucose and blood lipid were documented with evidence of interventions being provided.ResultsOf all 30 patients, none had shown compliance to all the parameters within the Lester Tool. 100% of the smoking status was documented, amongst which 78% were provided with interventions. 7% has lifestyle and diet status documented, of which 50% were given dietary advice. 80% had BMI documented, amongst which none were provided with any intervention. 90% had blood pressure documented, of which 50% were given any intervention. 40% had blood glucose documented, of which all were provided with intervention. 57% had blood lipid documented, of which none were provided with any intervention.ConclusionsOur results have shown the need of further awareness on the usefulness of the Lester Tool in an acute inpatient ward. Our recommendation would be to regularly train and educate inpatient staff to ensure that all the necessary parameters be monitored and provided with interventions.Disclosure of InterestNone Declared

Background RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM +ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. Methods We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm −/− mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm -loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. Results Rhamm -loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm -loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm −/− primary tumor clones that are enriched in lung metastases. Rhamm −/− tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM +ve tumor cells to a significantly greater extent than RHAMM −ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. Conclusion RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

Epithelial–mesenchymal transition (EMT) is a phenotypic conversion that facilitates organ morphogenesis and tissue remodeling. The authors of this Review discuss the phenomenon of EMT in relation to tumor development, and the function of EMT in promoting invasion and metastasis. The roles of ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT are also highlighted. Epithelial–mesenchymal transition (EMT) is a phenotypic conversion that facilitates organ morphogenesis and tissue remodeling in physiological processes, such as embryonic development and wound healing. A similar phenotypic conversion is also detected in fibrotic diseases and neoplasia, and is associated with disease progression. EMT in cancer epithelial cells often seems to be an incomplete and bidirectional process. In this Review, we discuss the phenomenon of EMT as it pertains to tumor development, focusing on exceptions to the commonly held rule that EMT promotes invasion and metastasis. We also highlight the role of RAS-controlled signaling mediators, ERK1, ERK2 and phosphatidylinositol 3-kinase, as microenvironmental responsive regulators of EMT. Key Points Fibroblast activity (e.g. desmoplasia and stromal transcriptomes) are associated with poor outcome in cancers Epithelial–mesenchymal transition (EMT) of epithelial cancer cells contributes to this activity in the peritumor stroma, and EMT is a subset of the more generalized cell phenotype plasticity exhibited by aggressive tumor cells Clear evidence for EMT of tumor cells in human tumors is rare, and this might be owing to its transient and dynamic nature The clinical significance of EMT is still under study but has been associated with the metastatic/invasive phenotype and specific breast carcinoma subtypes Study of EMT has focused on its role in active dissemination of tumor cells (e.g. migration and invasion), but emerging evidence suggests a broader functional role in tumor progression, including drug resistance and immune modulation RAS-regulated pathways connect regulation of EMT to the tumor microenvironment

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA–HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10–480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA ⁻/ˡᵒʷ vs. HA ʰⁱᵍʰ) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA–binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA ʰⁱᵍʰ subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA ⁻/ˡᵒʷ subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.

CD44 is a multi-functional receptor with multiple of isoforms engaged in modulation of cell trafficking and transmission of apoptotic signals. We have previously shown that injection of anti-CD44 antibody into NOD mice induced resistance to type 1 diabetes (T1D). In this communication we describe our efforts to understand the mechanism underlying this effect. We found that CD44-deficient NOD mice develop stronger resistance to T1D than wild-type littermates. This effect is not explained by the involvement of CD44 in cell migration, because CD44-deficient inflammatory cells surprisingly had greater invasive potential than the corresponding wild type cells, probably owing to molecular redundancy. We have previously reported and we show here again that CD44 expression and hyaluronic acid (HA, the principal ligand for CD44) accumulation are detected in pancreatic islets of diabetic NOD mice, but not of non-diabetic DBA/1 mice. Expression of CD44 on insulin-secreting β cells renders them susceptible to the autoimmune attack, and is associated with a diminution in β-cells function (e.g., less insulin production and/or insulin secretion) and possibly also with an enhanced apoptosis rate. The diabetes-supportive effect of CD44 expression on β cells was assessed by the TUNEL assay and further strengthened by functional assays exhibiting increased nitric oxide release, reduced insulin secretion after glucose stimulation and decreased insulin content in β cells. All these parameters could not be detected in CD44-deficient islets. We further suggest that HA-binding to CD44-expressing β cells is implicated in β-cell demise. Altogether, these data agree with the concept that CD44 is a receptor capable of modulating cell fate. This finding is important for other pathologies (e.g., cancer, neurodegenerative diseases) in which CD44 and HA appear to be implicated.

Impingement is a major source of dislocation and aseptic loosening in total hip arthroplasty (THA). We compared impingement free range of motion (ROM) using a novel computer navigated femur first approach to conventional THA. In addition, impingement between genders was also explored. In a retrospective analysis of 121 THA patients, subject-specific post-operative ROM was simulated using post-operative 3D-CT data, and compared with the benchmark ROM, essential for activities of daily living. Three parameters were defined to express both implant-to-implant (ITI) and bone-to-bone (BTB) impingement - coverage percentage, third angle, and impingement severity. Although coverage percentage was similar between the navigated and conventional group for both ITI (p = 0.69) and BTB (p = 0.82) impingement, third angle was significantly reduced in the navigation group for both ITI (p = 0.02) and BTB (p = 0.05) impingement. Impingement severity for both ITI (p = 0.01) and BTB (p = 0.05) was significantly decreased in the navigation group compared to the conventional. Impingement severity in men was considerably higher compared to women for both ITI (p = 0.002) and BTB (p = 0.02). Navigation guided femur first THA is able to improve alignment of ROM axis, and consequently, to reduce impingement in THA. Men seem to be more prone to impingement than women.

Mutation cluster analysis is critical for understanding certain mutational mechanisms relevant to genetic disease, diversity, and evolution. Yet, whole genome sequencing for detection of mutation clusters is prohibitive with high cost for most organisms and population surveys. Single nucleotide polymorphism (SNP) genotyping arrays, like the Mouse Diversity Genotyping Array, offer an alternative low-cost, screening for mutations at hundreds of thousands of loci across the genome using experimental designs that permit capture of de novo mutations in any tissue. Formal statistical tools for genome-wide detection of mutation clusters under a microarray probe sampling system are yet to be established. A challenge in the development of statistical methods is that microarray detection of mutation clusters is constrained to select SNP loci captured by probes on the array. This paper develops a Monte Carlo framework for cluster testing and assesses test statistics for capturing potential deviations from spatial randomness which are motivated by, and incorporate, the array design. While null distributions of the test statistics are established under spatial randomness via the homogeneous Poisson process, power performance of the test statistics is evaluated under postulated types of Neyman-Scott clustering processes through Monte Carlo simulation. A new statistic is developed and recommended as a screening tool for mutation cluster detection. The statistic is demonstrated to be excellent in terms of its robustness and power performance, and useful for cluster analysis in settings of missing data. The test statistic can also be generalized to any one dimensional system where every site is observed, such as DNA sequencing data. The paper illustrates how the informal graphical tools for detecting clusters may be misleading. The statistic is used for finding clusters of putative SNP differences in a mixture of different mouse genetic backgrounds and clusters of de novo SNP differences arising between tissues with development and carcinogenesis.