Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

Complex diffusive dynamics are often observed when one is investigating the mobility of macromolecules in living cells and other complex environments, yet the underlying physical or chemical causes of anomalous diffusion are often not fully understood and are thus a topic of ongoing research interest. Theoretical models capturing anomalous dynamics are widely used to analyze mobility data from fluorescence correlation spectroscopy and other experimental measurements, yet there is significant confusion regarding these models because published versions are not entirely consistent and in some cases do not appear to satisfy the diffusion equation. Further confusion is introduced through variations in how fitting parameters are reported. A clear definition of fitting parameters and their physical significance is essential for accurate interpretation of experimental data and comparison of results from different studies acquired under varied experimental conditions. This article aims to clarify the physical meaning of the time-dependent diffusion coefficients associated with commonly used fitting models to facilitate their use for investigating the underlying causes of anomalous diffusion. We discuss a propagator for anomalous diffusion that captures the power law dependence of the mean-square displacement and can be shown to rigorously satisfy the extended diffusion equation provided one correctly defines the time-dependent diffusion coefficient. We also clarify explicitly the relation between the time-dependent diffusion coefficient and fitting parameters in fluorescence correlation spectroscopy.

Background Nanoscale drug-delivery systems (DDSs) have great promise in tumor diagnosis and treatment. Platelet membrane (PLTM) biomimetic DDSs are expected to enhance retention in vivo and escape uptake by macrophages, as well as minimizing immunogenicity, attributing to the CD47 protein in PLTM sends “ don’t eat me ” signals to macrophages. In addition, P-selectin is overexpressed on the PLTM, which would allow a PLTM-biomimetic DDS to specifically bind to the CD44 receptors upregulated on the surface of cancer cells. Results In this study, porous nanoparticles loaded with the anti-cancer drug bufalin (Bu) were prepared from a chitosan oligosaccharide (CS)-poly(lactic-co-glycolic acid) (PLGA) copolymer. These were subsequently coated with platelet membrane (PLTM) to form PLTM-CS-pPLGA/Bu NPs. The PLTM-CS-pPLGA/Bu NPs bear a particle size of ~ 192 nm, and present the same surface proteins as the PLTM. Confocal microscopy and flow cytometry results revealed a greater uptake of PLTM-CS-pPLGA/Bu NPs than uncoated CS-pPLGA/Bu NPs, as a result of the targeted binding of P-selectin on the surface of the PLTM to the CD44 receptors of H22 hepatoma cells. In vivo biodistribution studies in H22-tumor carrying mice revealed that the PLTM-CS-pPLGA NPs accumulated in the tumor, because of a combination of active targeting effect and the EPR effect. The PLTM-CS-pPLGA/Bu NPs led to more effective tumor growth inhibition over other bufalin formulations. Conclusions Platelet membrane biomimetic nanoparticles played a promising targeted treatment of cancer with low side effect. Electronic supplementary material The online version of this article (10.1186/s12951-019-0494-y) contains supplementary material, which is available to authorized users.

Fluorescence fluctuation spectroscopy has become an important measurement tool for investigating molecular dynamics, molecular interactions, and chemical kinetics in biological systems. Although the basic theory of fluctuation spectroscopy is well established, it is not widely recognized that saturation of the fluorescence excitation can dramatically alter the size and profile of the fluorescence observation volume from which fluorescence fluctuations are measured, even at relatively modest excitation levels. A precise model for these changes is needed for accurate analysis and interpretation of fluctuation spectroscopy data. We here introduce a combined analytical and computational approach to characterize the observation volume under saturating conditions and demonstrate how the variation in the volume is important in two-photon fluorescence correlation spectroscopy. We introduce a simple approach for analysis of fluorescence correlation spectroscopy data that can fully account for the effects of saturation, and demonstrate its success for characterizing the observed changes in both the amplitude and relaxation timescale of measured correlation curves. We also discuss how a quantitative model for the observed phenomena may be of broader importance in fluorescence fluctuation spectroscopy.

Currently, most available treatments focus on alleviating the primary motor symptoms including bradykinesia, muscle stiffness, tremors at rest, and other nonmotor disturbances. [3] However, therapeutic effects become limited with disease progression. [4] Thus, the development of novel treatment strategies for the prevention and delay of PD progress is urgently needed. [5] Despite in-depth researches, the detailed etiology of neuronal degeneration in PD is still unclear and controversial. Furthermore, the debate regarding whether apoptosis contributes to neuronal loss in PD is ongoing. [6] Pyroptosis is relevant to PD, as the levels of interleukin (IL)-1β and IL-18 upregulated significantly in the cerebrospinal fluid of PD patients when compared to healthy controls. [7] Emerging evidence from human samples and animal models has demonstrated that neuroinflammatory mechanisms are deleterious factors in neurodegenerative diseases [8] and may be involved in the cascade of events leading to neuronal dopaminergic degeneration. [9] Neuroinflammation occurs in the early stage of PD and leads to dopaminergic neurons damage. [9] Nucleotide-binding domain and leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex composed of an NLRP3 sensor, apoptosis-associated speck-like protein (ASC, a signal adaptor), and caspase-1 protease. NLRP3 inflammasome is expressed in microglia, and plays a key role in the progression of PD. [10,11] In response to bacterial toxins, oxidative stress, or oligomeric/fibrillar α-syn aggregation, as well as other pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), the NLRP3 inflammasome assembles rapidly in microglia, resulting in the activation of caspase-1. Activated caspase-1 in turn cleaves the IL-1β precursor into the mature form of IL-1β, [12] thereby mediating proinflammatory responses and pyroptosis. [13] In 2015, the gasdermin protein was identified as a key factor for pyroptosis in inflammatory diseases, autoimmune diseases, and cancer, opening novel therapeutic avenues. [14] The introduction of pyroptosis-related agonists or antagonists is expected to improve the treatment efficacy of inflammatory diseases and may guide the development of better vaccine adjuvants or immunotherapy in the future. [15] However, the identification of Current pharmacological interventions for Parkinson's disease (PD) remain unsatisfactory in clinical settings. Inflammasome-mediated pyroptosis represents a potential therapeutic target for the alleviation of neurodegenerative diseases. The development of inflammasome-mediated pyroptosis agonists or antagonists may transform the treatment of neurodegenerative diseases. However, the identification of specific compounds that inhibit pyroptosis remains challenging. Herein, Prussian blue nanozyme (PBzyme) is revealed as a pyroptosis inhibitor to alleviate the neurodegeneration in mouse and cell models of PD. PBzyme protects the microglia and neurons against 1-methyl-4-phenyl-1...