189 research outputs found
Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand
Introduction
Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma.
Aims
To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines.
Results
Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both.
Conclusions
1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes
Intensive enteral nutrition is ineffective for individuals with severe alcoholic hepatitis treated with corticosteroids.
peer reviewedBACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a lifethreatening
disease for which adequate oral nutritional support
is recommended. We performed a randomized controlled trial to
determine whether the combination of corticosteroid and
intensive enteral nutrition therapy is more effective than corticosteroid
therapy alone in patients with severe AH. METHODS:
We enrolled 136 heavy consumers of alcohol (age, 18–75 y)
with recent onset of jaundice and biopsy-proven severe AH in
our study, performed at 18 hospitals in Belgium and 2 in
France, from February 2010 through February 2013. Subjects
were assigned randomly (1:1) to groups that received either
intensive enteral nutrition plus methylprednisolone or conventional
nutrition plus methylprednisolone (controls). In the
intensive enteral nutrition group, enteral nutrition was given
via feeding tube for 14 days. The primary end point was patient
survival for 6 months. RESULTS: In an intention-to-treat analysis,
we found no significant difference between groups in
6-month cumulative mortality: 44.4% of patients died in the
intensive enteral nutrition group (95% confidence interval [CI],
32.2%–55.9%) and 52.1% of controls died (95% CI, 39.4%–
63.4%) (P ¼ .406). The enteral feeding tube was withdrawn
prematurely from 48.5% of patients, and serious adverse
events considered to be related to enteral nutrition occurred in
5 patients. Regardless of group, a greater proportion of patients
with a daily calorie intake less than 21.5 kcal/kg/day died
(65.8%; 95% CI, 48.8–78.4) than patients with a higher intake
of calories (33.1%; 95% CI, 23.1%–43.4%) (P < .001).
CONCLUSIONS: In a randomized trial of patients with severe AH
treated with corticosteroids, we found that intensive enteral
nutrition was difficult to implement and did not increase survival.
However, low daily energy intake was associated with greater
mortality, so adequate nutritional intake should be a main goal for
treatment
Evolution and environment of the eastern linear pottery culture: A case study in the site of Polgár-Piócási-Dűlő
A salvage excavation preceding a major investment project was conducted in 2006–2007, during which associated settlement features of a Middle Neolithic, Eastern Linear Pottery Culture (Alföld Linearbandkeramik – ALBK) were uncovered in an area called Piócási-dűlő on the eastern outskirts of Polgár. The features of the ALBK settlement date from two periods. The cluster of multi-functional pits yielding a rich assortment of finds, the handful of post-holes and an unusual ritual well found in the southern part of the investigated area formed one unit from the earliest phase of the Middle Neolithic (ALBK I). The settlement’s other occupation can be assigned to the late phase of the Middle Neolithic (ALBK IV). Five houseplans representing the remains of timber-framed buildings outlined a distinct area with three multi-functional pits. Associated with the above features were 8 burials.
The preliminary archaeobotanical results from Polgár–Piócási-dűlő are based on the plant material found within the sediments of 11 archaeological structures, which mainly represent pits and a welI. It can be stated that the natural environment offered habitats in which oak trees dominated in the local vegetation, forming floodplain forests and wooded steppes. They also provided food in the form of fruits and formed an optimal habitat for domestic animals. Arable fields were probably also established in the vicinity of the settlements, suggested by findings of macroscopic plant remains that represented cultivated species.
In both settlement phases lithic production activities are manifested both by the local on-site lithic production and – most importantly – by the presence of imported, mainly mesolocal, raw materials that point to contacts with deposit areas, or off-site preliminary working of obsidian and limnoquartzites. The kit of harvesting tools and a large number of grinding stones – especially in the younger phase – for the preparation of plant food suggest a major role of plant cultivation
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