In situ cancer vaccines are under active clinical investigation, given their reported ability to eradicate both local and disseminated malignancies. Intratumoral vaccine administration is thought to activate a T cell-mediated immune response, which begins in the treated tumor and cascades systemically. In this study, we describe a PET tracer (64Cu-DOTA-AbOX40) that enabled noninvasive and longitudinal imaging of OX40, a cell-surface marker of T cell activation. We report the spatiotemporal dynamics of T cell activation following in situ vaccination with CpG oligodeoxynucleotide in a dual tumor-bearing mouse model. We demonstrate that OX40 imaging was able to predict tumor responses on day 9 after treatment on the basis of tumor tracer uptake on day 2, with greater accuracy than both anatomical and blood-based measurements. These studies provide key insights into global T cell activation following local CpG treatment and indicate that 64Cu-DOTA-AbOX40 is a promising candidate for monitoring clinical cancer immunotherapy strategies.

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b + CD45 + myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b + CD45 + cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut Reprints and permissions information is available at www.nature.com/reprints.

Neuroinflammation plays a key role in neuronal injury following ischemic stroke.Positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO) permits longitudinal, non-invasive visualization of neuroinflammation in both pre-clinical and clinical settings. Many TSPO tracers have been developed, however it is unclear which tracer is the most sensitive and accurate for monitoring the in vivo spatiotemporal dynamics of neuroinflammation across applications.Hence, there is a need for head-to-head comparisons of promising TSPO-PET tracers across different disease states. Accordingly, the aim of this study was to directly compare two promising second-generation TSPO tracers;

The Ras-MAPK pathway has an established role in neural development and synaptic signaling. Mutations in this pathway are associated with a collection of neurodevelopmental syndromes, Rasopathies; among these, Noonan syndrome (NS) is the most common (1:2000). Prior research has focused on identifying genetic mutations and cellular mechanisms of the disorder, however, effects of NS on the human brain remain unknown. Here, imaging and cognitive data were collected from 12 children with PTPN11-related NS, ages 4.0-11.0 years (8.98 ± 2.33) and 12 age- and sex-matched typically developing controls (8.79 ± 2.17). We observe reduced gray matter volume in bilateral corpus striatum (Cohen's d = -1.0:-1.3), reduced surface area in temporal regions (d = -1.8:-2.2), increased cortical thickness in frontal regions (d = 1.2-1.3), and reduced cortical thickness in limbic regions (d = -1.6), including limbic structures integral to the circuitry of the hippocampus. Further, we find high levels of inattention, hyperactivity, and memory deficits in children with NS. Taken together, these results identify effects of NS on specific brain regions associated with ADHD and learning in children. While our research lays the groundwork for elucidating the neural and behavioral mechanisms of NS, it also adds an essential tier to understanding the Ras-MAPK pathway's role in human brain development.

Recollection has long been thought to play a key role in associative recognition tasks. Evidence that associative recollection might be a threshold process has come from analyses of the associative recognition Receiver Operating Characteristic (ROC). Specifically, the ROC is not as curvilinear as a signal-detection theory requires. In addition, the z-ROC is usually curvilinear, as a threshold recollection model requires, not linear, as a signal-detection model requires. In Experiment 1, word pairs were strengthened at study, which yielded a curvilinear ROC and a linear z-ROC (in accordance with signal-detection theory). This result suggests that associative recognition performance was based on a continuous variable, one that likely consists either of unitized familiarity or continuous recollection. The Remember/Know procedure and an unexpected cued recall test suggested that the more curvilinear ROC in the strong condition was mainly due to increased recollection. In Experiment 2, word pairs were presented for an old/new recognition decision before being presented for an associative recognition decision. When pairs consisting of items not recognized as having been seen on the list were removed from the analysis, the ROC again became curvilinear, the z-ROC again became linear, and most associative recognition decisions were associated with Remember judgments. These findings suggest that the curvilinear z-ROC often observed on associative recognition tests results from noise, as a mixture signal-detection model assumes, and that recollection is a continuous process that yields a curvilinear ROC that is well characterized by signaldetection theory. Continuous Recollection vs. Unitized Familiarity in Associative RecognitionRecognition memory decisions are widely thought to be based either on the recollection of specific contextual details or on a context-free sense of familiarity (Atkinson & Juola, 1973;Jacoby, 1991;Mandler, 1980;Yonelinas, 2002). To investigate the nature of the recollection process, associative recognition procedures are commonly used, and this is true in both experimental psychology (e.g., Clark, 1992;Clark & Hori, 1995;Hockley, 1992;Hockley & Consoli, 1999;Hockley & Cristi, 1996;Nobel & Shiffrin, 2001;Verde, 2004;Yonelinas, 1997) and cognitive neuroscience (e.g., Giovanello, Verfaellie, & Keane, 2003;Habib & Nyberg, 2008;Haskins, Yonelinas, Quamme, & Ranganath, 2008;Sauvage, Fortin, Owens, Yonelinas, & Eichenbaum, 2008;Speer & Curran, 2007;Turriziani, Fadda, Caltagirone, & Carlesimo, 2004;Stark, Bayley, & Squire, 2002). In a typical version of this procedure, participants first study a list of word pairs and then, on a subsequent recognition Address correspondence for this article to John T. Wixted, Department of Psychology, 0109, University of California, San Diego, La Jolla, CA 92093-0109. jwixted@ucsd.edu. Phone: 858-534-3956. Fax: 858-534-7190. The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreadin...

B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, < 0.05). Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls ( < 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increasedCu-rituximab uptake in CNS tissues corresponded with elevated B cells. B cells can be detected in the CNS of EAE mice usingCu-rituximab PET. Results from these studies warrant further investigation of Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic.

Supplemental Figure 1. Time activity curves (TACs) from dynamic PET scans for (A) spinal cord and (B) whole brain at 7 days post-fracture do not exhibit differences in tracer kinetic trajectory using mixed model statistical tests.

We strongly recommend that adult patients with CDAD undergo early surgery, before the development of shock and need for vasopressors. We conditionally recommend total or subtotal colectomy (vs. partial colectomy or other surgery) when the diagnosis of The Centers for Disease Control and Prevention is known.