Cytomegalovirus (CMV) infection is an

The precise role of lipid peroxidation in the pathogenesis of alcoholic liver disease is still being debated. To explore the issue, this study was undertaken to investigate the status of lipid peroxidation, antioxidants and prooxidants at two discrete stages of experimental alcoholic liver disease. Male Wistar rats were intragastrically fed a high-fat diet plus ethanol for 5 or 16 wk (the duration that resulted in initiation of centrilobular liver necrosis or liver fibrosis, respectively). Lipid peroxidation was assessed in isolated microsomes and mitochondria with three parameters: malondialdehyde equivalents as determined by thiobarbituric acid assay, conjugated diene formation and 4-hydroxynonenal as a 2,4-dinitrophenylhydrazone derivative. To assess antioxidant systems, hepatic concentrations of glutathione, methionine and alpha-tocopherol were determined. The concentration of nonheme iron, a known prooxidant, was also measured. At wk 5, centrilobular liver necrosis was already evident in the ethanol-fed animals, with two- or threefold increases in plasma AST and ALT levels. At this stage, neither malondialdehyde equivalents nor conjugated diene values were elevated, and the 4-hydroxynonemal level was below 0.2 nmol/mg protein. Hepatic concentrations of methionine and alpha-tocopherol in these animals were increased two- and threefold, respectively, whereas the reduced glutathione level remained unchanged. When alcoholic liver disease had progressed to perivenular or bridging fibrosis at wk 16, all three parameters of lipid peroxidation showed consistent increases that were accompanied by significant reductions in the hepatic glutathione and methionine levels. Interestingly, the control animals pair-fed with the high-fat diet also had significantly elevated 4-hydroxynonenal levels at wk 16 compared to the wk 5 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Key Points• CML LSC demonstrate increased IL-1 receptor expression and enhanced signaling response.• Inhibition of IL-1 signaling using the antagonist IL-1RA enhances targeting of CML LSC in combination with TKI.Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow. We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1 receptor accessory protein and IL-1 receptor type 1 (IL-1R1), and enhanced sensitivity to IL-1-induced NF-kB signaling compared with normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment and that IL-1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML. (Blood. 2016;128(23):2671-2682

Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized. Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-gamma) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR-gamma gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma. Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.

The use of the Tsukamoto-French rat model of alcoholic liver disease facilitated pathological, physiological, biochemical and cell biological experiments that examined the validity of some of the existing hypotheses for pathogenesis of alcoholic liver necrosis and fibrosis. Results obtained to date strongly support the contribution of centrilobular hypoxia as a pathogenetic mechanism of alcoholic liver necrosis. The enhanced hepatic lipid peroxidation was not evident at the early stage of ethanol-induced liver necrosis but could be demonstrated at the late stage when the liver damage progressed to liver fibrosis. This suggests that the lipid peroxidation may not be an important mechanism of alcoholic liver necrosis but may be an initiation factor for liver fibrogenesis as recently proposed by others (88). The high-fat diet appears to have promoting effects on both induction of alcoholic liver necrosis and stimulation of liver fibrogenesis. The former may be related to the induction of MEOS by the high-fat diet and consequent centrilobular hypoxia caused by inadequately compensated hepatic overuse of oxygen. The latter can be mediated through sensitization of Ito cells by a high-fat diet. We propose that Kupffer cell-derived TGF beta is, at least in part, responsible for some of phenotypical changes of Ito cells associated with their activation. Our model provides maximal experimental control and induces the discrete stages of alcoholic liver injury that can be reproduced with its pathological evolution telescoped into a short time. Because of these features, replication of the experimental conditions in different laboratories is possible so that results can be validly compared through precise standardization of the experimental protocols. This model requires some training in implantation and maintenance of the gastric catheter. However, the training can be easily attained by anyone who has experience in animal surgery. Another requirement is the initial fund to acquire infusion devices and metabolism cages. Once this equipment is purchased, however, the maintenance cost is low. Even if the initial expenses are included, the cost per animal is relatively inexpensive when compared with the cost involved in the use of larger animals such as baboons or pigs. Since administration of diet and ethanol (or isocaloric glucose solution) is precisely controlled by infusion pumps, this system makes unnecessary the measurement of diet consumption that has to be done daily for each animal with other methods.(ABSTRACT TRUNCATED AT 250 WORDS)