No abstract

Liver fibrosis, the response to chronic liver injury, results from the activation of mesenchymal cells to fibrogenic myofibroblasts. We have recently shown that two key myofibroblast precursor populations, hepatic stellate cells and portal fibroblasts, undergo activation in culture in response to increasing substrate stiffness. We therefore hypothesized that alterations in liver stiffness precede myofibroblast activation and fibrosis in vivo as well. To test this hypothesis, we induced fibrosis in rats by twice weekly injections of carbon tetrachloride (CCl4) and then killed the animals at various time points ranging from 3 to 70 days after the initiation of injury. The shear storage modulus of the whole liver was measured on fresh tissue; fixed and frozen tissue from the same livers was used to quantify fibrosis. We observed that liver stiffness increased immediately and continued to increase, leveling out by day 28. Fibrosis, measured histologically by trichrome staining as well as by quantitative sirius red staining, increased with time, although these increases were delayed relative to changes in stiffness. There was no direct correlation between stiffness and fibrosis at early or late time points. Treatment of a second cohort of rats with the lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), partially prevented early increases in liver stiffness. We concluded that increases in liver stiffness precede fibrosis and potentially myofibroblast activation. Liver stiffness appears to result from matrix cross-linking and possibly other unknown variables in addition to matrix quantity. We suggest that increased liver stiffness may play an important role in initiating the early stages of fibrosis.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update was to rapidly review the emerging evidence and provide timely expert recommendations regarding the management of patients with inflammatory bowel disease during the coronavirus disease 2019 pandemic. This expert commentary was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely perspective on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology.

Endoscopic submucosal dissection (ESD) is an established endoscopic resection method in Asian countries, which is increasingly practiced in Europe and by early adopters in the United States for removal of early cancers and large lesions from the luminal gastrointestinal tract. The intent of this expert review is to provide an update regarding the clinical practice of ESD with a particular focus on its use in the United States. This review is framed around the 16 best practice advice points agreed upon by the authors, which reflect landmark and recent published articles in this field. This expert review also reflects our experience as advanced endoscopists with extensive experience in performing and teaching others to perform ESD in the United States. Best Practice Advice 1: Endoscopic submucosal dissection should be recognized as a mature endoscopic technique that enables complete removal of lesions that are too large for en bloc endoscopic mucosal resection or are at increased risk of containing cancer. Best Practice Advice 2: The safety and feasibility of endoscopic submucosal dissection for early gastric cancer is well established. The absolute indications for curative endoscopic resection include moderately and well-differentiated, nonulcerated, mucosal lesions that are ≤2 cm in size. Best Practice Advice 3: Other relative (expanded) indications for gastric endoscopic submucosal dissection include moderately and well-differentiated superficial cancers that are >2 cm, lesions ≤3 cm with ulceration or that contain early submucosal invasion, and poorly differentiated superficial cancers ≤2 cm in size. The risk of lymph node metastasis when endoscopic submucosal dissection is performed for these indications is higher than when it is performed for absolute indications but remains acceptably low. Best Practice Advice 4: Endoscopic submucosal dissection may be considered in selected patients with Barrett's esophagus with the following features: large or bulky area of nodularity, lesions with a high likelihood of superficial submucosal invasion, recurrent dysplasia, endoscopic mucosal resection specimen showing invasive carcinoma with positive margins, equivocal preprocedural histology, and intramucosal carcinoma. Best Practice Advice 5: Endoscopic submucosal dissection is the primary modality for treatment of squamous cell dysplasia and cancer confined to the superficial esophageal mucosa. Any degree of submucosal invasion caries an increased risk of lymph node metastasis and alternative/additional therapy should be considered. Best Practice Advice 6: Duodenal endoscopic submucosal dissection is associated with an increased risk of intraprocedural perforation and delayed adverse events. Duodenal endoscopic submucosal dissection should be limited to endoscopists with extensive experience in performing endoscopic submucosal dissection in other locations. It is strongly suggested that endoscopists in the United States refrain from performing duodenal endoscopic submucosal dissection during the early phase of their endo...

Perepelyuk M, Terajima M, Wang AY, Georges PC, Janmey PA, Yamauchi M, Wells RG. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 304: G605-G614, 2013. First published January 17, 2013 doi:10.1152/ajpgi.00222.2012.-Liver fibrosis is characterized by excessive deposition of extracellular matrix proteins by myofibroblasts derived from hepatic stellate cells and portal fibroblasts. Activation of these precursors to myofibroblasts requires matrix stiffness, which results in part from increased collagen crosslinking mediated by lysyl oxidase (LOX) family proteins. The aims of this study were to characterize the mechanical changes of early fibrosis, to identify the cells responsible for LOX production in early injury, and to determine which cells in normal liver produce collagens and elastins, which serve as substrates for LOXs early after injury. Hepatocytes and liver nonparenchymal cells were isolated from normal and early-injured liver and examined immediately for expression of LOXs and matrix proteins. We found that stellate cells and portal fibroblasts were the major cellular sources of fibrillar collagens and LOXs in normal liver and early after injury (1 day after bile duct ligation and 2 and 7 days after CCl 4 injury). Activity assays using stellate cells and portal fibroblasts in culture demonstrated significant increases in LOX family enzymatic activity as cells became myofibroblastic. LOX family-mediated deoxypyridinoline and pyridinoline cross-links increased after CCl 4-mediated injury. There was a significant association between liver stiffness (as quantified by the shear storage modulus G=) and deoxypyridinoline levels; increased deoxypyridinoline levels were also coincident with significantly increased elastic resistance to large strain deformations, consistent with increased cross-linking of the extracellular matrix. These data suggest a model in which the liver is primed to respond quickly to injury, activating potential mechanical feed-forward mechanisms.collagen cross-linking; liver fibrosis; pyridinoline; deoxypyridinoline; extracellular matrix PATHOLOGICAL FIBROSIS is characterized by excessive accumulation of extracellular matrix (ECM) proteins, most notably fibrillar collagens. The majority of ECM in organ fibrosis is deposited by myofibroblasts, proliferative and motile cells characterized by expression of ␣-smooth muscle actin (␣-SMA), which migrate to the site of injury or differentiate from preexisting cells in the organ. In the liver, the major myofibroblast precursor cells are hepatic stellate cells and portal fibroblasts.Myofibroblast differentiation from precursor cells requires mechanical tension. This has been shown in vitro for general fibroblast-to-myofibroblast activation (14), as well as for hepatic stellate cell and portal fibroblast activation to myofibroblasts in the liver (19,36) and suggests that increases in liver stiffness precede myofi...

We report a multilayer solution-processed blue light-emitting diode based on colloidal core/shell CdS/ZnS nanocrystal quantum dots (QDs). At a low-operating voltage of 5.5 V, the device emits spectrally pure blue radiation at 460 nm with a narrow full-width-at-half-maximum bandwidth of 20 nm and high brightness up to 1600 cd/m2. Broad-band, long-wavelength emission from the polymer components and deep traps in the QDs are minimized to less than 5% of the total emission.

These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP. ClinicalTrials.gov: NCT02509416.

We report a novel drug delivery system composed of layer-by-layer (LBL) milk protein casein (CN) coated iron oxide nanoparticles. Doxorubicin (DOX) and indocyanine green (ICG) were selected as model drug molecules, which were incorporated into the inner polymeric layer, and subsequently coated with casein. The resulting casein coated iron oxide nanoparticles (CN-DOX/ICG-IO) were stable in the acidic gastric condition with the presence of gastric protease. On the other hand, the loaded drugs were released when the casein outer layer was gradually degraded by the intestinal protease in the simulated intestine condition. Such unique properties enable maintenance of the bioactivity of the drugs and thus enhance the drug delivery efficiency. Ex vivo experiments showed that the LBL CN-DOX-IO improved the translocation of DOX across microvilli and its absorption in the small intestine sacs. In vivo imaging of mice that were orally administered with these LBL CN-ICG-IO nanostructures further confirmed that the reported drug delivery vehicles could pass the stomach without significant degradation, and then accumulated in the small intestine. In addition, the magnetic iron oxide nanoparticle core offered an MRI contrast enhancing capability for in vivo imaging guided drug delivery. Therefore, the reported LBL CN-DOX/ICG-IO is a promising oral drug delivery nanoplatform, especially for drugs that are poorly soluble in water or degradable in the gastric environment.