long-term administration of the agent. The copper level Trientine dihydrochloride (trientine) is an alternative in the liver of treated rats was reduced by 33% at 87 medicinal copper chelating agent for patients with Wilweeks of age. Development of HCC in LEC rats might be son's disease of penicillamine intolerance. We examined partly, but not totally, because of copper accumulation. the effects of trientine on the spontaneous development No effects on the levels of copper, iron, or zinc in the of hepatitis and hepatic tumors, by its short-term and liver of LEA rats was detected, and no adverse effects long-term administration to Long-Evans cinnamon were detected in either LEC or LEA rats after both short-(LEC) rats with an accumulation of copper in the liver, and long-term administration of trientine in drinking as animal models of Wilson's disease. Male rats were water. (HEPATOLOGY 1996;23:764-770.) given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppmThe mutant strain of rats, LEC (Long-Evans cinnafor 52 weeks, from 8 to 87 weeks of age in the long-term mon) was first found after sudden death of a number experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high of them at 18-20 weeks of age, following their developlevels of plasma transaminases (glutamic oxaloacetic ment of hepatitis. This strain of rats consistently develtransaminase [GOT], glutamic pyruvic transaminase ops hepatitis with varying degrees of severity. The hep-[GPT]), and on pathological examination, hepatocyte de-atitis is characterized by an increase in the serum struction was observed. Histological findings revealed levels of glutamic oxaloacetic transaminase (GOT) and that short-term administration of trientine inhibited the glutamic pyruvic transaminase (GPT), hyperbilirubidevelopment of hepatitis remarkably. The plasma GOT nemia, and massive necrosis without an inflammatory and GPT levels of treated animals were only slightly cells response. [1][2][3] Most of the rats surviving the hepati- In the long-term administration of trientine, the inci-accumulate copper in their livers. 5 By linkage analysis dence of hepatic cell carcinoma (HCC) in the treated rats of F 1 back-crosses, we found that the genetic trait leadwas 67% that of the untreated LEC rats, and the number ing to the accumulation of copper in the liver is tightly of HCCs per rat in the treated group was 0.7 { 0.5, being linked with development of hepatitis. 6 Linkage analysignificantly lower as compared with 4.7 { 3.5 in the sis of F 1 back-crosses has also suggested that the gene untreated rats. Additionally, the development of cholan-responsible for Wilson's disease (Wc1/pWD), which engiofibrosis in LEC rats was completely prevented by codes a copper transporting P-type ATPase (ATP7B), is a candidate gene for hepatitis development in LEC rats. 7,8 Actually, a deletion in the rat Atp7b was found. 9Abbreviations: LEC, Lon...

Room-temperature operations of rechargeable Mg coin-cell batteries have been achieved using a spinel MgMn2O4 powder having a large specific surface area > 200 m2 g–1 and more than 90% porosity with a triple-tiered 3D open-channel network.

Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.

Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of LEA rats was detected, and no adverse effects were detected in either LEC or LEA rats after both short- and long-term administration of trientine in drinking water.

The collective migration of vascular endothelial cells plays important roles in homeostasis and angiogenesis. Oxygen tension in vivo is a key factor affecting the cellular dynamics. We previously reported hypoxic conditions promote the internalization of vascular endothelial (VE)-cadherin and increase the collective migration of vascular endothelial cells. However, the mechanism through which cells regulate collective migration as affected by oxygen tension is not fully understood. Here, we investigated oxygen-dependent collective migration, focusing on intracellular protein p21-activated kinase (PAK) and hypoxia-inducing factor (HIF)-1α. The results indicate that the oxygen-dependent variation of the migration speed of vascular endothelial cells is mediated by the regulation of VE-cadherin through the PAK pathway, as well as other mechanisms via HIF-1α, especially under extreme hypoxic conditions.