Immediate Reversal of Dabigatran by Idarucizumab Prior to Laboratory and Imaging Results in Acute Stroke

We report a case of intravenous thrombolysis in acute ischemic stroke of anterior choroidal artery following the antagonization of dabigatran with idarucizumab. No secondary complication, like hemorrhagic or thrombotic/thrombembolic event, of neither idarucizumab nor subsequent intravenous thrombolysis emerged. The recent approval of idarucizumab enables intravenous thrombolysis despite preexisiting oral anticoagulation with dabigatran, but raises the question of the optimal management and work flow of patients under medication with dabigatran and with acute neurological deficit, highly suspicious for an acute cerebrovascular event. In contrast to hitherto case reports and series, here, we explicitly refrained from awaiting the results of the thrombin time, as a marker for present anticoagulation by dabigatran, as well as the results of cerebral imaging before administration of idarucizumab. Based on the presented case we propose this approach to minimize door-to-needle time of intravenous thrombolysis in acute ischemic stroke and thus to enhance the chance for a good outcome

A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition

Dissociation of visual extinction and neglect in the left hemisphere.

Visual neglect and extinction are two distinct visuospatial attention deficits that frequently occur after right hemisphere cerebral stroke. However, their different lesion profiles remain a matter of debate. In the left hemisphere, a domain-general dual-loop model with distinct computational abilities onto which several cognitive functions may project, has been proposed: a dorsal stream for sensori-motor mapping in time and space and a ventral stream for comprehension and representation of concepts. We wondered whether such a distinction may apply to visual extinction and neglect in left hemisphere lesions. Of 165 prospectively studied patients with acute left hemispheric ischemic stroke with a single lesion on MRI, 122 had no visuospatial attention deficit, 10 had extinction, 31 neglect and 2 had both, visual extinction and neglect. Voxel-based-lesion-symptom mapping (VLSM, FDR<.05) showed a clear anatomical dissociation. Extinction occurred after damage to the parietal cortex (anterior bank of the intraparietal sulcus, inferior parietal lobe, and supramarginal gyrus), while visual neglect occurred after damage mainly to the temporal lobe (superior and middle temporal lobe, anterior temporal pole), inferior ventral premotor cortex, frontal operculum, angular gyrus, and insula. Direct comparison of both conditions linked extinction to intraparietal sulcus and supramarginal gyrus (FDR<.05). Thus, in the left hemisphere extinction seems to be related to dorsal stream lesions, whereas neglect maps more on the ventral stream. These data cannot be generalized to the right hemisphere. However, a domain-general point-of-view may stimulate discussion on visuospatial attention processing also in the right hemisphere

A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer

© 2015 Nature America, Inc. All rights reserved. Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.Link_to_subscribed_fulltex

Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer

SummaryOncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC

Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders

Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits