Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells

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The geology of part of the Snake River Canyon and adjacent areas in Northeastern Oregon and Western Idaho

The mapped area lies between the Wallowa Mountains of northeastern Oregon and the Seven Devils Mountains of western Idaho. Part of the Snake River canyon is included. A composite stratigraphic section includes at least 30,000 feet of strata. Pre- Tertiary and Tertiary strata are separated by a profound unconformity. Pre -Tertiary layered rocks are mostly Permian and Triassic volcaniclastic and volcanic flow rocks. At least four pre -Tertiary intrusive suites occur. Tertiary rocks are Miocene and Pliocene plateau basalts. Quaternary glacial materials and stream deposits locally mantle the older rocks. Permian ( ?) rocks of the Windy Ridge Formation are the oldest rocks and consist of 2,000 to 3,000 feet of keratophyre, quartz keratophyre, and keratophric pyroclastic rocks. Unconformably ( ?) overlying the Windy Ridge Formation are 8,000 to 10,000 feet of volcaniclastic rocks and minor volcanic flow rocks of the Hunsaker Creek Formation of Middle Permian (Leonardian and Wordian) age. Spilitic flow rocks of the Kleinschmidt Volcanics are interlayered with and in part overlie the Hunsaker Creek Formation and comprise a sequence about 2,000 to 3,000 feet thick. The Paleozoic layered rocks were intruded by the Holbrook - Irondyke intrusives, composed of keratophyre porphyry, quartz keratophyre porphyry, diabase, and gabbro. The Paleozoic rocks were deformed by an orogeny between Middle Permian and Middle Triassic time. Plutonic rocks (Oxbow Complex) of gabbro, quartz diorite, diorite, and albite granite were intruded during Early Triassic (7) time. Movements along the Oxbow -Cuprum shear zone occurred during and after the intrusions. Middle Triassic (Ladinian) spilitic flow rocks and volcaniclastic rocks of the Grassy Ridge Formation overlie the older rocks with angular unconformity. Thicknesses are 3,000 to 4,000 feet in the northeast part of the map area; no rocks of the Grassy Ridge Formation are exposed in the southwest part. The Imnaha Formation of Late Triassic (Karnian) age overlies the Permian strata unconformably near Fish Lake in the western part of the area. The Doyle Creek Formation of Late Triassic (Karnian) age conformably overlies the Grassy Ridge Formation in the Snake River and Imnaha River canyons and may interfinger with the Imnaha Formation east of Fish Lake. The Doyle Creek Formation ranges in thickness from 3,000 to 5,000 feet and includes two members - the Ashby Creek Conglomerate and the Piedmont Point Member. The Martin Bridge Formation, represented by 1,750 feet of Late Triassic (Norian) limestone, conformably overlies the Doyle Creek Formation. At least two intrusive events apparently occurred during the Jurassic Period. The Jurassic ( ?) intrusives, were emplaced before regional metamorphism and consist of hypabyssal dikes and sills of diorite, quartz diorite, and dacite and andesite porphyries. Subsequently, the Upper ( ?) Jurassic intrusives were emplaced during a late stage of regional metamorphism and are represented by small stocks of gabbro, norite, quartz diorite, and gran - odiorite porphyry. A major orogeny during Middle and Late ( ?) Jurassic time deformed the rocks. Regional metamorphism produced mineral assemblages characteristic of the greenschist facies. Columbia River Basalt, 2,000 to 3,000 feet thick, erupted from fissures during late Miocene and early Pliocene time and covered an old erosion surface. Pliocene - Pleistocene uplift, alpine glaciation, and extensive stream erosion are responsible for the present topography

Activin/Nodal Inhibition Alone Accelerates Highly Efficient Neural Conversion from Human Embryonic Stem Cells and Imposes a Caudal Positional Identity

Background Neural conversion from human embryonic stem cells (hESCs) has been demonstrated in a variety of systems including chemically defined suspension culture, not requiring extrinsic signals, as well as in an adherent culture method that involves dual SMAD inhibition using Noggin and SB431542 (an inhibitor of activin/nodal signaling). Previous studies have also determined a role for activin/nodal signaling in development of the neural plate and anterior fate specification. We therefore sought to investigate the independent influence of SB431542 both on neural commitment of hESCs and positional identity of derived neural progenitors in chemically defined substrate-free conditions. Methodology/Principal Findings We show that in non-adherent culture conditions, treatment with SB431542 alone for 8 days is sufficient for highly efficient and accelerated neural conversion from hESCs with negligible mesendodermal, epidermal or trophectodermal contamination. In addition the resulting neural progenitor population has a predominantly caudal identity compared to the more anterior positional fate of non-SB431542 treated cultures. Finally we demonstrate that resulting neurons are electro-physiologically competent. Conclusions This study provides a platform for the efficient generation of caudal neural progenitors under defined conditions for experimental study

A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial.

BACKGROUND: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response. METHODS: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion. RESULTS: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes. CONCLUSION: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials

Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.

Trastuzumab Duration questionnaire. The questionnaire that was completed by the oncologists. (PDF 476 kb

Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells

The difficulty in isolating and propagating functional primary cholangiocytes is a major limitation in the study of biliary disorders and the testing of novel therapeutic agents. To overcome this problem, we have developed a platform for the differentiation of human pluripotent stem cells (hPSCs) into functional cholangiocyte-like cells (CLCs). We have previously reported that our 26-d protocol closely recapitulates key stages of biliary development, starting with the differentiation of hPSCs into endoderm and subsequently into foregut progenitor (FP) cells, followed by the generation of hepatoblasts (HBs), cholangiocyte progenitors (CPs) expressing early biliary markers and mature CLCs displaying cholangiocyte functionality. Compared with alternative protocols for biliary differentiation of hPSCs, our system does not require coculture with other cell types and relies on chemically defined conditions up to and including the generation of CPs. A complex extracellular matrix is used for the maturation of CLCs; therefore, experience in hPSC culture and 3D organoid systems may be necessary for optimal results. Finally, the capacity of our platform for generating large amounts of disease-specific functional cholangiocytes will have broad applications for cholangiopathies, in disease modeling and for screening of therapeutic compounds.This work was funded by ERC starting grant Relieve IMDs (L.V., N.R.F.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.R.F.H., F.S.), the Evelyn trust (N.R.F.H.) and the EU Fp7 grant TissuGEN (M.C.d.B.). F.S. was supported by an Addenbrooke's Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship