Numerous diseases, recently reported to associate with elevated microvesicle/ microparticle (MP) counts, have also long been known to be characterized by accelerated immune complex (IC) formation. The goal of this study was to investigate the potential overlap between parameters of protein complexes (eg, ICs or avidinbiotin complexes) and MPs, which might perturb detection and/or isolation of MPs. In this work, after comprehensive characterization of MPs by electron microscopy, atomic force microscopy, dynamic lightscattering analysis, and flow cytometry, for the first time, we drive attention to the fact that protein complexes, especially insoluble ICs, overlap in biophysical properties (size, light scattering, and sedimentation) with MPs. This, in turn, affects MP quantification by flow cytometry and purification by differential centrifugation, especially in diseases in which IC formation is common, including not only autoimmune diseases, but also hematologic disorders, infections, and cancer. These data may necessitate reevaluation of certain published data on patient-derived MPs and contribute to correct the clinical laboratory assessment of the presence and biologic functions of MPs in health and disease. (Blood. 2011;117(4):e39-e48) IntroductionMembrane vesicles are small subcellular structures surrounded by a phospholipid bilayer. Their release by various cell types is enhanced during activation and apoptosis. 1 They represent heterogeneous structures and can be classified into several groups depending on their size, antigenic features, and mechanism of cellular release. 1 The two best characterized categories include exosomes and microvesicles/microparticles (MPs). Both populations are characterized by the exposure of phosphatidylserine, which allows annexin-V (AX) to bind to these-lipid surfaces. 1 Exosomes are composed of small, 50-to 100-nm-sized structures released on exocytosis of multivesicular bodies. 1 The diameter of MPs, formed by membrane blebbing, is described to be 100 to 1000 nm 2 . However, precise definitions of MPs are still lacking. 1,2 MPs are found in various biologic fluids, including blood plasma, 3 urine, 4 and synovial fluid (SF). 5,6 Numerous flow cytometry (FC) studies using blood plasma have shown correlation of MP counts with human cardiovascular 7 and autoimmune diseases, 8 hematologic disorders, 9 and cancer. 10 Of particular interest, autoimmune diseases were reported to be characterized by elevated levels of MPs. 11 The assessment of exosomes and MPs is complicated by the presence of further known categories of membrane bound subcellular structures, such as apoptotic vesicles, exosome-like vesicles, membrane particles, and ectosomes. 1 There is a substantial size overlap among the aforementioned vesicle categories, and the size distribution of a given vesicle preparation may also be affected by the method used for their isolation. 3,12,13 Recently, attempts have been made to standardize isolation and detection protocols for membrane vesicles. 3,14 Up until now, no systemat...

Breast cancer is a leading cause of death among women worldwide. Dysbiosis, an aberrant composition of the microbiome, characterizes breast cancer. In this review we discuss the changes to the metabolism of breast cancer cells, as well as the composition of the breast and gut microbiome in breast cancer. The role of the breast microbiome in breast cancer is unresolved, nevertheless it seems that the gut microbiome does have a role in the pathology of the disease. The gut microbiome secretes bioactive metabolites (reactivated estrogens, short chain fatty acids, amino acid metabolites, or secondary bile acids) that modulate breast cancer. We highlight the bacterial species or taxonomical units that generate these metabolites, we show their mode of action, and discuss how the metabolites affect mitochondrial metabolism and other molecular events in breast cancer. These metabolites resemble human hormones, as they are produced in a “gland” (in this case, the microbiome) and they are subsequently transferred to distant sites of action through the circulation. These metabolites appear to be important constituents of the tumor microenvironment. Finally, we discuss how bacterial dysbiosis interferes with breast cancer treatment through interfering with chemotherapeutic drug metabolism and availability.

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA–oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

Plasmonic structures open novel avenues in photodetector development. Optimized illumination configurations are reported to improve p-polarized light absorptance in superconducting-nanowire single-photon detectors (SNSPDs) comprising short- and long-periodic niobium-nitride (NbN) stripe-patterns. In OC-SNSPDs consisting of ~quarter-wavelength dielectric layer closed by a gold reflector the highest absorptance is attainable at perpendicular incidence onto NbN patterns in P-orientation due to E-field concentration at the bottom of nano-cavities. In NCAI-SNSPDs integrated with nano-cavity-arrays consisting of vertical and horizontal gold segments off-axis illumination in S-orientation results in polar-angle-independent perfect absorptance via collective resonances in short-periodic design, while in long-periodic NCAI-SNSPDs grating-coupled surface waves promote EM-field transportation to the NbN stripes and result in local absorptance maxima. In NCDAI-SNSPDs integrated with nano-cavity-deflector-array consisting of longer vertical gold segments large absorptance maxima appear in 3p-periodic designs due to E-field enhancement via grating-coupled surface waves synchronized with the NbN stripes in S-orientation, which enable to compensate fill-factor-related retrogression.

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