Osteoblastic flare in a patient with advanced gastric cancer after treatment with pemetrexed and oxaliplatin: implications for response assessment with RECIST criteria

<p>Abstract</p> <p>Background</p> <p>The RECIST guidelines are commonly used in phase II and III clinical trials. The correct definition of response can be controversial in some situations, as in the case we describe.</p> <p>Case presentation</p> <p>A 43 year-old man with advanced gastric cancer was enrolled in a phase II trial where he was treated with pemetrexed 500 mg/m²plus oxaliplatin 120 mg/m²every 3 weeks. At baseline, the target lesions were lymph-nodes, and the non-target lesions were small pulmonary nodules. At first re-evaluation, the target lesions showed partial response and the non-target lesions showed complete response, but new diffuse osteoblastic lesions appeared. The investigator decided to continue treatment until the second re-evaluation. CT scan confirmed the response of the target and non-target lesions, while the osteoblastic lesions did not change.</p> <p>Conclusion</p> <p>The appearance of osteoblastic lesions after an active antitumor treatment, a phenomenon known as flare, can complicate the definition of the best overall response using RECIST criteria. This possibility should be considered by oncologists involved in clinical trials.</p

Identification of nonclassical properties of light with multiplexing layouts

In Sperling et al. [Phys. Rev. Lett. 118, 163602 (2017)], we introduced and applied a detector-independent method to uncover nonclassicality. Here, we extend those techniques and give more details on the performed analysis. We derive a general theory of the positive-operator-valued measure that describes multiplexing layouts with arbitrary detectors. From the resulting quantum version of a multinomial statistics, we infer nonclassicality probes based on a matrix of normally ordered moments. We discuss these criteria and apply the theory to our data which are measured with superconducting transition-edge sensors. Our experiment produces heralded multiphoton states from a parametric down-conversion light source. We show that the known notions of sub-Poisson and sub-binomial light can be deduced from our general approach, and we establish the concept of sub-multinomial light, which is shown to outperform the former two concepts of nonclassicality for our data

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR)

<p>Abstract</p> <p>Background</p> <p>Recent reports indicate the existence of breast cancer cells expressing very high levels of the Arylhydrocarbon receptor (AhR), a ubiquitous intracellular receptor best known for mediating toxic action of dioxin and related pollutants. Positive correlation between the degree of AhR overexpression and states of increasing transformation of mammary epithelial cells appears to occur in the absence of any exogenous AhR ligands. These observations have raised many questions such as why and how AhR is overexpressed in breast cancer and its physiological roles in the progression to advanced carcinogenic transformation. To address those questions, we hypothesized that AhR overexpression occurs in cells experiencing deficiencies in normally required estrogen receptor (ER) signaling, and the basic role of AhR in such cases is to guide the affected cells to develop orchestrated cellular changes aimed at substituting the normal functions of ER. At the same time, the AhR serves as the mediator of the cell survival program in the absence of ER signaling.</p> <p>Methods</p> <p>We subjected two lines of Michigan Cancer Foundation (MCF) mammary epithelial cells to 3 different types ER interacting agents for a number of passages and followed the changes in the expression of AhR mRNA. The resulting sublines were analyzed for phenotypical changes and unique molecular characteristics.</p> <p>Results</p> <p>MCF10AT1 cells continuously exposed to 17-beta-estradiol (E2) developed sub-lines that show AhR overexpression with the characteristic phenotype of increased proliferation, and distinct resistance to apoptosis. When these chemically selected cell lines were treated with a specific AhR antagonist, 3-methoxy-4-nitroflavone (MNF), both of the above abnormal cellular characteristics disappeared, indicating the pivotal role of AhR in expressing those cellular phenotypes. The most prominent molecular characteristics of these AhR overexpressing MCF cells were found to be overexpression of ErbB2 and COX-2. Furthermore, we could demonstrate that suppression of AhR functions through anti-AhR siRNA or MNF causes the recovery of ERalpha functions.</p> <p>Conclusion</p> <p>One of the main causes for AhR overexpression in these MCF breast cancer cells appears to be the loss of ERalpha functions. This phenomenon is likely to be based on the mutually antagonistic relationship between ER and AhR.</p

Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories

In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphse plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered

Patterns of subnet usage reveal distinct scales of regulation in the transcriptional regulatory network of Escherichia coli

The set of regulatory interactions between genes, mediated by transcription factors, forms a species' transcriptional regulatory network (TRN). By comparing this network with measured gene expression data one can identify functional properties of the TRN and gain general insight into transcriptional control. We define the subnet of a node as the subgraph consisting of all nodes topologically downstream of the node, including itself. Using a large set of microarray expression data of the bacterium Escherichia coli, we find that the gene expression in different subnets exhibits a structured pattern in response to environmental changes and genotypic mutation. Subnets with less changes in their expression pattern have a higher fraction of feed-forward loop motifs and a lower fraction of small RNA targets within them. Our study implies that the TRN consists of several scales of regulatory organization: 1) subnets with more varying gene expression controlled by both transcription factors and post-transcriptional RNA regulation, and 2) subnets with less varying gene expression having more feed-forward loops and less post-transcriptional RNA regulation.Comment: 14 pages, 8 figures, to be published in PLoS Computational Biolog

Affect in mathematics education

There are two different uses for the word “affect” in behavioral sciences. Often it is used as an overarching umbrella concept that covers attitudes, beliefs, motivation, emotions, and all other noncognitive aspects of human mind. In this article, however, the word affect is used in a more narrow sense, referring to emotional states and traits. A more technical definition of emotions, states, and traits will follow later.Peer reviewe

Electric-field-induced coherent coupling of the exciton states in a single quantum dot

The signature of coherent coupling between two quantum states is an anticrossing in their energies as one is swept through the other. In single semiconductor quantum dots containing an electron-hole pair the eigenstates form a two-level system that can be used to demonstrate quantum effects in the solid state, but in all previous work these states were independent. Here we describe a technique to control the energetic splitting of these states using a vertical electric field, facilitating the observation of coherent coupling between them. Near the minimum splitting the eigenstates rotate in the plane of the sample, being orientated at 45{\deg} when the splitting is smallest. Using this system we show direct control over the exciton states in one quantum dot, leading to the generation of entangled photon pairs

Three-dimensional reconstruction of myocardial contrast perfusion from biplane cineangiograms by means of linear programming techniques

The assessment of coronary flow reserve from the instantaneous distribution of the contrast agent within the coronary vessels and myocardial muscle at the control state and at maximal flow has been limited by the superimposition of myocardial regions of interest in the two-dimensional images. To overcome these limitations, we are in the process of developing a three-dimensional (3D) reconstruction technique to compute the contrast distribution in cross sections of the myocardial muscle from two orthogonal cineangiograms. To limit the number of feasible solutions in the 3D-reconstruction space, the 3D-geometry of the endo- and epicardial boundaries of the myocardium must be determined. For the geometric reconstruction of the epicardium, the centerlines of the left coronary arterial tree are manually or automatically traced in the biplane views. Next, the bifurcations are detected automatically and matched in these two views, allowing a 3D-representation of the coronary tree. Finally, the circumference of the left ventricular myocardium in a selected cross section can be computed from the intersection points of this cross section with the 3D coronary tree using B-splines. For the geometric reconstruction of the left ventricular cavity, we envision to apply the elliptical approximation technique using the LV boundaries defined in the two orthogonal views, or by applying more complex 3D-reconstruction techniques including densitometry. The actual 3D-reconstruction of the contrast distribution in the myocardium is based on a linear programming technique (Transportation model) using cost coefficient matrices. Such a cost coefficient matrix must contain a maximum amount of a priori information, provided by a computer generated model and updated with actual data from the angiographic views. We have only begun to solve this complex problem. However, based on our first experimental results we expect that the linear programming approach with advanced cost coefficient matrices and computed model will lead to a