Oncogenic 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.

SummaryWe show that BRAFV600E 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 BrafV600E 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.

smotic demyelination syndrome (ODS) was first described in 1959 by Adams and Victor, who reported "pontine myelinolysis" in alcoholic patients (1). On pathophysiological considerations, and as an increasing number of manifestation sites in addition to the pons were detected, central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) were combined into "osmotic demyelination syndrome". Exact epidemiological data are still lacking, as there is not always a clear distinction between ODS and a prior or underlying disease. Furthermore, ODS is not always detected radiologically. As a result, the introduction of magnetic resonance imaging (MRI) led to increasing incidences of ODS, with the demonstration of oligosymptomatic as well as asymptomatic manifestations. Overall, ODS accounts for 0.4% to 0.56% of all neurological admissions to tertiary referral hospitals and 0.06% of all medical hospital admissions (2-4). MRI-based studies describe SummaryBackground: Osmotic demyelination syndrome (ODS), which embraces central pontine myelinolysis (CPM) and extrapontine myelinosis (EPM), is often underdiagnosed in clinical practice, but can be fatal. In this article, we review the etiology, pathophysiology, clinical features, diagnosis, treatment, and prognosis of ODS.Methods: Pertinent publications from the years 1959 to 2018 were retrieved by a selective search in PubMed.Results: The most common cause of ODS is hyponatremia; particular groups of patients, e.g., liver transplant recipients, are also at risk of developing ODS. The pathophysiology of ODS consists of cerebral apoptosis and loss of myelin due to osmotic stress. Accordingly, brain areas that are rich in oligodendrocytes and myelin tend to be the most frequently affected. Patients with ODS often have a biphasic course, the first phase reflecting the underlying predisposing illness and the second phase reflecting ODS itself, with pontine dysfunction, impaired vigilance, and movement disorders, among other neurological abnormalities. The diagnostic modality of choice is magnetic resonance imaging (MRI) of the brain, which can also be used to detect oligosymptomatic ODS. The current mainstay of management is prevention; treatment strategies for manifest ODS are still experimental. The prognosis has improved as a result of MRI-based diagnosis, but ODS can still be fatal (33% to 55% of patients either die or remain permanently dependent on nursing care). Conclusion:ODS is a secondary neurological illness resulting from a foregoing primary disease. Though rare overall, it occurs with greater frequency in certain groups of patients. Clinicians of all specialties should therefore be familiar with the risk constellations, clinical presentation, and prevention of ODS. The treatment of ODS is still experimental at present, as no evidence-based treatment is yet available.

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.