Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression.

The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development.

Integrin signalling regulates YAP and TAZ to control skin homeostasis.

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain.

Morphogen signaling is critical for the growth and patterning of tissues in embryos and adults, but how morphogen signaling gradients are generated in tissues remains controversial. The morphogen Nodal was proposed to form a long-range signaling gradient via a reaction-diffusion system, on the basis of differential diffusion rates of Nodal and its antagonist Lefty. Here we use a specific zebrafish Nodal biosensor combined with immunofluorescence for phosphorylated Smad2 to demonstrate that endogenous Nodal is unlikely to diffuse over a long range. Instead, short-range Nodal signaling activation in a temporal window is sufficient to determine the dimensions of the Nodal signaling domain. The size of this temporal window is set by the differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty translation by the microRNA miR-430. Thus, temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm.

An unusual cause of vomiting in an infant of 3 months of age.

This is a 3-month-old infant with a diagnosis of acute cholecystitis presenting with projectile vomiting and no fever and no abdominal pain.

Adapting the "managing by walking around" methodology as a leadership strategy to communicate a hospital-wide strategic plan.

Metropolitan Hospital Center (MHC) in East Harlem, New York, has undergone significant leadership changes within the past few years, and the current leadership team developed a long-term strategic plan for the organization that it wanted to effectively communicate to all hospital staff. The spread of information is a challenge at MHC, as it is in many hospitals, because of the large number of staff working various shifts, and the inability of staff to leave their units at the same time to attend general staff meetings. Because of the recent success of the hospital's Executive WalkRounds Program and Breakthough Program, which embody principles of the leadership strategy Managing By Walking Around (MBWA), the senior leadership team decided to roll out their new strategic plan in a 2-week series of rounds to each unit/department throughout the hospital during each shift. Utilizing this method, 69 percent of MHC staff attended the rounds, and 88.9 percent of management level staff and 64.5 percent of unionized/labor who participated in the hospital's Employee Satisfaction Survey stated that they understood the hospital's new strategic plan. MHC's successful strategy is easily applicable within other similar settings.