Explore the vast range of titles available.

Background Signal regulatory protein alpha (SIRPα) is an important regulator of innate and adaptive immune responses by promoting T cell and macrophage activation and macrophage adhesion (multi-nucleated giant cell formation) while preventing phagocytic cell death to sustain inflammatory responses. Methods We determined whether SIRPα is expressed in sarcoidosis tissue and whether ELA026, a humanized SIRP-blocking Ab, suppresses sarcoidosis granuloma formation by attenuating inflammation, promoting cell death, and suppressing adhesion during granuloma formation. Results Based upon immunohistochemistry, SIRPα stained in greater abundance in giant cells, monocytes, macrophages and dendritic cells in sarcoidosis lung tissue than in normal lung, lung cancer, non-granulomatous lung diseases and non-sarcoidosis granulomatous diseases. All these differences were statistically significant except for non-sarcoidosis granulomatous lung diseases. We then leveraged an ex vivo human granuloma model, wherein PBMCs from sarcoidosis patients are activated to form granulomas within 7 days, to determine whether ELA026 attenuated granuloma formation, based upon MIPAR image analysis, and associated cytokine responses. A matching isotype antibody (ELA099) that does not bind SIRPs was a negative control; prednisone was a positive control. As hypothesized, pre-treatment (day 0) or post-treatment (day 4) with ELA026 or prednisone (not ELA099) caused dose-dependent suppression of sarcoidosis granuloma formation by day 7. Unexpectedly, ELA026 only modestly reduced TNFα production when used as a pre-treatment and did not suppress IL-1β release or promote cell death, as reflected by no LDH release. Conclusions SIRPα is robustly expressed in monocyte/macrophage lineages within human sarcoidosis tissues, and inhibition of SIRPs (ELA026) suppresses sarcoidosis granuloma formation by preventing macrophage adhesion/aggregation.

Cell aggregates are a tool for in vitro studies of morphogenesis, cancer invasion, and tissue engineering. They respond to mechanical forces as a complex rather than simple liquid. To change an aggregate's shape, cells have to overcome energy barriers. If cell shape fluctuations are active enough, the aggregate spontaneously relaxes stresses (\"fluctuation-induced flow\"). If not, changing the aggregate's shape requires a sufficiently large applied stress (\"stress-induced flow\"). To capture this distinction, we develop a mechanical model of aggregates based on their cellular structure. At stress lower than a characteristic stress τ*, the aggregate as a whole flows with an apparent viscosity η*, and at higher stress it is a shear-thinning fluid. An increasing cell-cell tension results in a higher η* (and thus a slower stress relaxation time tc). Our constitutive equation fits experiments of aggregate shape relaxation after compression or decompression in which irreversibility can be measured; we find tc of the order of 5 h for F9 cell lines. Predictions also match numerical simulations of cell geometry and fluctuations. We discuss the deviations from liquid behavior, the possible overestimation of surface tension in parallel-plate compression measurements, and the role of measurement duration.

Multiple myeloma (MM) is considered to be one of the hematological malignancies formed by excessive and abnormal proliferation of plasmocytes. Among other parameters, several blood tests are used to diagnose multiple myeloma. The hemorheological profile in multiple myeloma is not widely studied. Hemorheology includes the study of measuring the deformability and aggregation of erythrocytes, blood viscosity, and sedimentation rate. The degree of deformability of blood cells is necessary to maintain proper vital functions. Proper deformability of red blood cells ensures proper blood circulation, tissue oxidation and carbon dioxide uptake. The aim of the study was to compare morphology and blood rheology parameters in patients with MM and healthy individuals. The study included 33 patients with MM, and 33 healthy subjects of the same age. The hematological blood parameters were evaluated using ABX MICROS 60 hematology analyzer. The LORCA Analyzer to study erythrocyte aggregation and deformability. Patients with MM had lower red blood cells count (RBC) (9.11%) (p < 0.001) and half time of total aggregation (T1/2) (94.29%) (p < 0.001) values and higher mean corpuscular volume (MCV) (5.50%) (p < 0.001), aggregation index (AI) (68.60%) (p < 0.001), total extent of aggregation (AMP) (87.92%) (p < 0.001) values than the healthy control group. Aggregation in patients with MM is different compared to healthy individuals. It was observed that the percentage of cell aggregation is almost 50% higher than in the control group. The study of morphology, aggregation and deformability of erythrocytes in patients with suspected MM may be helpful in making clinical decisions.

Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44 cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation. Using patient-derived xenograft (PDX) models, we established an tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering. We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation and reduced lung metastasis . Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR. Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.

Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

Background Maturation of complex N-glycans involves the action of Golgi mannosidases and plays a major role in cancer progression. We recently showed a favourable prognostic role of α-mannosidase MAN1A1 in breast cancer mainly caused by alteration of certain adhesion molecules. Methods We analysed the protein expression of MAN1A1 in ovarian cancer ( n  = 204) using western blot and studied the impact of MAN1A1 itself and of MAN1A1-related glycosylation on the prognostic relevance of two adhesion molecules. Functional consequences of mannosidase inhibition using kifunensine and MAN1A1 knock out were investigated in ovarian cancer cells in vitro. Results Patients with high MAN1A1 expression in tumours showed significantly shorter RFS than those with low-MAN1A1 levels. Moreover, high MAN1A1 expression correlated significantly with advanced stage, lymph node involvement and distant metastasis. Further, the glycosylated adhesion molecule ALCAM reveals a significant adverse prognostic effect only in the presence of high MAN1A1 expression. In spheroid-formation assays, mannosidase inhibition and especially MAN1A1 knock out led to strong reduction of tumour cell aggregation. Conclusions Our study demonstrates the unfavourable prognostic role of MAN1A1 in ovarian cancer, probably caused by an altered ability of spheroid formation, and the strong influence of this glycosylation enzyme on the prognostic impact of ALCAM.

Cell rearrangements are fundamental mechanisms driving large-scale deformations of living tissues. In three-dimensional (3D) space-filling cell aggregates, cells rearrange through local topological transitions of the network of cell-cell interfaces, which is most conveniently described by the vertex model. Since these transitions are not yet mathematically properly formulated, the 3D vertex model is generally difficult to implement. The few existing implementations rely on highly customized and complex software-engineering solutions, which cannot be transparently delineated and are thus mostly non-reproducible. To solve this outstanding problem, we propose a reformulation of the vertex model. Our approach, called Graph Vertex Model (GVM), is based on storing the topology of the cell network into a knowledge graph with a particular data structure that allows performing cell-rearrangement events by simple graph transformations. Importantly, when these same transformations are applied to a two-dimensional (2D) polygonal cell aggregate, they reduce to a well-known T1 transition, thereby generalizing cell-rearrangements in 2D and 3D space-filling packings. This result suggests that the GVM’s graph data structure may be the most natural representation of cell aggregates and tissues. We also develop a Python package that implements GVM, relying on a graph-database-management framework Neo4j . We use this package to characterize an order-disorder transition in 3D cell aggregates, driven by active noise and we find aggregates undergoing efficient ordering close to the transition point. In all, our work showcases knowledge graphs as particularly suitable data models for structured storage, analysis, and manipulation of tissue data.

Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 -MNPs) have been widely used in clinical diagnosis. Hemocompatibility of the nanoparticles is usually evaluated by hemolysis. However, hemolysis assessment does not measure the dysfunctional erythrocytes with pathological changes on the unbroken cellular membrane. The aim of this study is to evaluate the use of suicidal death of erythrocytes (i.e. eryptosis indices) as a novel predictive and prognostic parameter and to determine the impact of Fe 3 O 4 -MNPs on cellular membrane structure and the rheology properties of blood in circulation. Our results showed that phosphatidylserine externalization assessment was significantly more sensitive than classical hemolysis testing in evaluating hemocompatibility. Although no remarkable changes of histopathology, hematology and serum biochemistry indices were observed in vivo , Fe 3 O 4 -MNPs significantly affected hemorheology indices including erythrocyte deformation index, erythrocyte rigidity index, red blood cell aggregation index and erythrocyte electrophoresis time, which are related to the mechanical properties of the erythrocytes. Oxidative stress induced calcium influx played a critical role in the eryptotic activity of Fe 3 O 4 -MNPs. This study demonstrated that Fe 3 O 4 -MNPs cause eryptosis and changes in flow properties of blood, suggesting that phosphatidylserine externalization can serve as a predictive parameter for hemocompatibility assay.

Yeast flocculation is a community-building cell aggregation trait that is an important mechanism of stress resistance and a useful phenotype for brewers; however, it is also a nuisance in many industrial processes, in clinical settings, and in the laboratory. Chemostat-based evolution experiments are impaired by inadvertent selection for aggregation, which we observe in 35% of populations. These populations provide a testing ground for understanding the breadth of genetic mechanisms Saccharomyces cerevisiae uses to flocculate, and which of those mechanisms provide the biggest adaptive advantages. In this study, we employed experimental evolution as a tool to ask whether one or many routes to flocculation are favored, and to engineer a strain with reduced flocculation potential. Using a combination of whole genome sequencing and bulk segregant analysis, we identified causal mutations in 23 independent clones that had evolved cell aggregation during hundreds of generations of chemostat growth. In 12 of those clones, we identified a transposable element insertion in the promoter region of known flocculation gene FLO1, and, in an additional five clones, we recovered loss-of-function mutations in transcriptional repressor TUP1, which regulates FLO1 and other related genes. Other causal mutations were found in genes that have not been previously connected to flocculation. Evolving a flo1 deletion strain revealed that this single deletion reduces flocculation occurrences to 3%, and demonstrated the efficacy of using experimental evolution as a tool to identify and eliminate the primary adaptive routes for undesirable traits.

In this study we demonstrated that exposure of Escherichia coli ( E. coli ) to terahertz (THz) radiation resulted in a change in the activities of the tdcABCDEFGR and matA–F genes (signs of cell aggregation), gene yjjQ (signs of suppression of cell motility), dicABCF , FtsZ , and minCDE genes (signs of suppression of cell division), sfmACDHF genes (signs of adhesin synthesis), yjbEFGH and gfcA genes (signs of cell envelope stabilization). Moreover, THz radiation induced E. coli csg operon genes of amyloid biosynthesis. Electron microscopy revealed that the irradiated bacteria underwent increased aggregation; 20% of them formed bundle-like structures consisting of two to four pili clumped together. This could be the result of changes in the adhesive properties of the pili. We also found aberrations in cell wall structure in the middle part of the bacterial cell; these aberrations impaired the cell at the initial stages of division and resulted in accumulation of long rod-like cells. Overall, THz radiation was shown to have adverse effects on bacterial populations resulting in cells with abnormal morphology.