Diffusion-weighted MRI of renal cell carcinoma, upper tract urothelial carcinoma, and renal infection: a pictorial review

Diffusion-weighted (DW) magnetic resonance imaging (MRI) is a functional imaging technique that derives image contrast from differences in water molecule diffusion within tissues. DW MRI helps detect and characterize renal and urothelial malignancies, may help in differentiating some benign from malignant renal masses, and can also recognize renal and upper urinary tract infections. Patients precluded from receiving intravenous contrast agents may particularly benefit from this technique.     

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.     

The SUUR protein is involved in binding of SU(VAR)3–9 and methylation of H3K9 and H3K27 in chromosomes of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

In the present work, we found that the SUUR protein is required for the SU(VAR)3–9 enzyme to bind to the salivary gland polytene chromosomes. The SuUR mutation results in loss of SU(VAR)3–9 on the chromosomes, whereas artificial expression of the SuUR gene restores its binding. The SUUR protein is also involved in methylation of the residues H3K9 and H3K27. However, mono-, di-, and tri-methylated forms of H3K9 and H3K27 behave differently in various chromosomal domains in response to the SuUR mutation. Euchromatin and chromosome 4 are almost completely deprived of mono-, di-, and tri-methylation of H3K9. In the chromocenter, mono-methylation is reduced, di-methylation shows no noticeable changes, and tri-methylation is lost. Furthermore, mono- and di-methylation of H3K27 are not influenced by the SuUR mutation, whereas tri-methylation is lost in the chromocenter. Artificial expression of the SuUR gene on the SuUR ^– background restores the pattern of methylated residues characteristic for the wild type.     

Wip1, an oncogene targeting tumor suppressors expressed in intestinal stem cells

Wip1 phosphatase (PPM1D) has oncogenic properties and is implicated in a variety of cancer types, including gastrointestinal. Like Mdm2, Wip1 normally functions to resolve stress responses, such as after DNA damage, and return the cell to its normal, unstressed state. It is expressed in somatic as well as stem cells, with relatively high expression in intestinal stem cells. Loss of normal APC function and other events early in the carcinogenic process trigger a stress-like state often referred to as oncogenic stress. Wip1 can dampen protective responses to such stress through dephosphorylation of key activating sites in important tumor suppressors, such as p53. Even normal levels of Wip1 affect tumor suppression, because Wip1-deficient mice are markedly tumor resistant in a variety of tumor-prone models, including APC^min. Unlike Mdm2-null mice, Wip1-null mice have a relatively mild phenotype, so development of Wip1 inhibitors may be well tolerated in vivo.     

Regulation of dendritic cell differentiation and function by Notch and Wnt pathways

Summary: The process of dendritic cell differentiation is governed by a tightly controlled signaling network regulated by cytokines and direct interaction between progenitor cells and bone marrow stroma. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. Wnt pathway is activated by soluble proteins produced by bone marrow stroma. Until recently, the role of Notch and Wnt signaling in the development of myeloid cells and dendritic cells in particular remained unclear. In this review, we discuss recent exciting findings that shed light on the critical role of Notch and Wnt pathways, their interaction in differentiation and function of dendritic cells, and their impact on immune responses.     

Probabilistic discrimination of relative stimulus features in mice

During perceptual decision-making, the brain encodes the upcoming decision and the stimulus information in a mixed representation. Paradigms suitable for studying decision computations in isolation rely on stimulus comparisons, with choices depending on relative rather than absolute properties of the stimuli. The adoption of tasks requiring relative perceptual judgments in mice would be advantageous in view of the powerful tools available for the dissection of brain circuits. However, whether and how mice can perform a relative visual discrimination task has not yet been fully established. Here, we show that mice can solve a complex orientation discrimination task in which the choices are decoupled from the orientation of individual stimuli. Moreover, we demonstrate a typical discrimination acuity of 9°, challenging the common belief that mice are poor visual discriminators. We reached these conclusions by introducing a probabilistic choice model that explained behavioral strategies in 40 mice and demonstrated that the circularity of the stimulus space is an additional source of choice variability for trials with fixed difficulty. Furthermore, history biases in the model changed with task engagement, demonstrating behavioral sensitivity to the availability of cognitive resources. In conclusion, our results reveal that mice adopt a diverse set of strategies in a task that decouples decision-relevant information from stimulus-specific information, thus demonstrating their usefulness as an animal model for studying neural representations of relative categories in perceptual decision-making research.

The focus of perceptual decision-making research is to reveal the processes by which sensory information is used to inform decisions and guide behavior (1). When considering the neural underpinnings of these processes, both sensory and decision information are often found to be encoded by the same neural populations, making the identification of unique neural signatures of decision-making challenging (2–4). To overcome this problem, behavioral tasks that rely on relative rather than absolute values of stimulus properties can be advantageous (5–8). In these tasks, the same amount of information about the correct choice can be given by many combinations of stimuli, which allows the separation of the sensory and decision components of neural activity. Effectively, these tasks introduce invariance of choice categories with respect to specific stimuli.In visual decision-making, a task with these characteristics is an orientation discrimination task featuring invariance with respect to specific orientations, which requires a subject to make relative orientation comparisons of stimuli. The convenience of this task relates to the well-characterized neural encoding of stimulus orientations in the striatal visual cortex of all mammalian species (9, 10). The mouse animal model, which features an unmatched abundant set of experimental tools for the dissection of neural circuits (11–13), performing a relative orientation discrimination task could be a promising study system for examining the neural mechanisms underlying sensory decision-making. However, whether mice can be trained in a relative orientation discrimination task, and which strategies they may adopt in this task, have been unknown.Here, we implemented a two-alternative forced-choice (2AFC) discrimination task for mice in which they had to report the more vertical orientation of two simultaneously presented grating stimuli. Importantly, the vertical orientation was not shown in the majority of trials, and the same value of “relative verticality” was given by many pairs of oriented gratings. Animals could adopt similar but not optimal choice strategies, albeit at the cost of water reward, which allowed us to explore a continuum of naturally arising strategies. To characterize these strategies, we designed a probabilistic choice model that quantified how animals combined information from the two stimuli. We expanded the model to account for trial history–induced biases and analyzed the dependence of these biases on the engagement state of the animal. Finally, with the help of the model, we estimated orientation discrimination acuity and showed that mice perform this task with high levels of accuracy and sensitivity to small differences in orientation.While the use of complex visual discrimination tasks in mice can be challenging because of the difficulty in training animals, modeling their choice strategies, parameterizing visual objects, and finding their neural representations, our complex discrimination task addresses these problems by extending the existing orientation discrimination protocols (14–18). We suggest that our task will allow for the exploration of links between neural and behavioral variability (19) in the context of heuristics and suboptimal choice strategies in rodent perceptual decision-making (20).