Summary Interactions between developmental signaling pathways govern the formation and function of stem cells. Prostaglandin (PG) E2 regulates vertebrate hematopoietic stem cells (HSC). Similarly, the Wnt signaling pathway controls HSC self-renewal and bone marrow repopulation. Here, we show that wnt reporter activity in zebrafish HSCs is responsive to PGE2 modulation, demonstrating a direct interaction in vivo. Inhibition of PGE2 synthesis blocked wnt-induced alterations in HSC formation. PGE2 modified the wnt signaling cascade at the level of β-catenin degradation through cAMP/PKA-mediated stabilizing phosphorylation events. The PGE2/Wnt interaction regulated murine stem and progenitor populations in vitro in hematopoietic ES cell assays and in vivo following transplantation. The relationship between PGE2 and Wnt was also conserved during regeneration of other organ systems. Our work provides the first in vivo evidence that Wnt activation in stem cells requires PGE2, and suggests the PGE2/Wnt interaction is a master regulator of vertebrate regeneration and recovery.

Parenteral fish-oil-based fat emulsions are safe and may be effective in the treatment of parenteral nutrition-associated liver disease.

OBJECTIVE The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (IFE) in the treatment of PNALD. SUMMARY AND BACKGROUND DATA Parenteral nutrition-associated liver disease (PNALD) can be a lethal complication in children with short bowel syndrome (SBS). IFE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. METHODS We performed an open-labeled trial of a fish-oil IFE in 42 infants with SBS who developed cholestasis (serum direct bilirubin > 2 mg/dL) while receiving soybean IFE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean IFE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin ≤2 mg/dL). RESULTS Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared to 12 deaths and 6 transplants in the controls (P=0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19/38 patients in the fish oil cohort vs. 2/36 patients in the controls. Based on Cox models, subjects receiving fish oil-IFE experienced reversal of cholestasis 6 times faster (95% CI=2.0,37.3) than those receiving soybean IFE. The provision of fish oil IFE was not associated with hypertriglyceridemia, coagulopathy, essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal INR levels were more common among controls. CONCLUSIONS Fish oil IFE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Here we report the reversal of cholestasis in 2 infants with intestinal failure and parenteral nutrition-associated liver disease. Treatment involved the substitution of a conventional intravenous fat emulsion with one containing primarily omega-3 fatty acids. Biochemical tests of liver function improved significantly. One child was removed from the liver transplantation list because of improved hepatic function, and the second child had complete resolution of cholestasis while solely on parenteral nutrition. This suggests that fat emulsions made from fish oils may be an effective means of treating and preventing this often-fatal condition. A randomized, controlled trial is necessary to study the efficacy of this new approach to parenteral nutrition-associated liver disease.

Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer-TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.

Developmental signaling pathways hold the keys to unlocking the promise of adult tissue regeneration, and to inhibiting carcinogenesis. Patients with mutations in the Adenomatous Polyposis Coli (APC) gene are at increased risk of developing hepatoblastoma, an embryonal form of liver cancer, suggesting that Wnt affects hepatic progenitor cells. To elucidate the role of APC loss and enhanced Wnt activity in liver development, we examined APC mutant and wnt inducible transgenic zebrafish. APC(+/-) embryos developed enlarged livers through biased induction of hepatic gene programs and increased proliferation. Conversely, APC(-/-) embryos formed no livers. Blastula transplantations determined that the effects of APC loss were cell autonomous. Induction of wnt modulators confirmed biphasic consequences of wnt activation: endodermal pattern formation and gene expression required suppression of wnt signaling in early somitogenesis; later, increased wnt activity altered endodermal fate by enhancing liver growth at the expense of pancreas formation; these effects persisted into the larval stage. In adult APC(+/-) zebrafish, increased wnt activity significantly accelerated liver regeneration after partial hepatectomy. Similarly, liver regeneration was significantly enhanced in APC(Min/+) mice, indicating the conserved effect of Wnt pathway activation in liver regeneration across vertebrate species. These studies reveal an important and time-dependent role for wnt signaling during liver development and regeneration.

acid-rich vegetable oil-based enteral and parenteral nutrition is still widely used, newer lipid 53 components such as medium-chain triglycerides and olive oil are safe and well tolerated. Fish 54 oil (FO)-enriched enteral and parenteral nutrition appears to be well tolerated and confers 55 additional clinical benefits, particularly in surgical patients, due to its anti-inflammatory and 56immune-modulating effects. Whilst the evidence base is not conclusive, there appears to be a 57 potential for FO-enriched nutrition, particularly administered peri-operatively, to reduce the rate 58 of complications and intensive care unit (ICU) and hospital stay in surgical ICU patients. The 59 evidence for FO-enriched nutrition in non-surgical ICU patients is less clear regarding its clinical 60 benefits and additional, well-designed large-scale clinical trials need to be conducted in this 61 area. The ESPEN Expert Group supports the use of olive oil and FO in nutrition support in 62 surgical and non-surgical ICU patients but considers that further research is required to provide 63 a more robust evidence base. 64 65 Page 4 of 77 Nutrition support of the critically ill patient 66Patients in an intensive care unit (ICU) are heterogeneous and include surgical and medical 67 patients, mechanically-ventilated or non-ventilated, obese or undernourished, preterm infants to 68 older adults, requiring either short-term or long-term intensive care [1]. Nutrition support is 69 critical in maintaining homeostasis in the ICU patient and to provide nutrients for the 70 maintenance of lean body mass as well as repair and maintenance of organ function and 71 support of defense and healing processes. 72Enteral nutrition (EN) comprises specialized liquid nutrition delivered through a nasogastric or 73 post-pyloric feeding tube into the stomach or small intestine (duodenum/jejunum), respectively 74[2]. The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend 75 that EN should be given to all ICU patients who are not expected to be taking a full oral diet 76 within three days [3]. 77Whilst ESPEN acknowledges that there are no definitive data supporting the early use of EN in 78 terms of clinical outcomes, its guidelines recommend that hemodynamically stable critically ill 79 patients who have a functioning gastrointestinal tract should be fed early (< 24 hours) using an 80 appropriate amount of feed [3]. Early initiation of EN is also recommended by the American 81 Society for Parenteral and Enteral Nutrition (ASPEN) and the Canadian Society of Critical Care 82Medicine (SCCM) [4], as well as the European Society of Intensive Care Medicine (ESICM) [5]. 83Administration of early EN in critically ill patients appears to also have a positive economic 84 impact, with analysis suggesting that it is associated with significantly reduced costs relating to 85 reduction in ICU stay and duration of mechanical ventilation compared with standard care [6]. 86There are a number of nutritional and non-nutritional benefits associa...

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