LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) are nuclear receptors that respond to cholesterol metabolites and regulate the expression of a subset of glucocorticoid target genes. Here, we show LXRβ is required to mediate many of the negative side effects of glucocorticoids. Mice lacking LXRβ (but not LXRα) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system. In vivo, LXRα/β knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRβ was required for glucocorticoid-induced recruitment of the glucocorticoid receptor to the PEPCK promoter. These findings suggest a new avenue for the design of safer glucocorticoid drugs through a mechanism of selective glucocorticoid receptor transactivation.     

Efficacy of therapy of different variants of anaplastic large T-cell lymphomas

AIM: To compare efficacy of NHL-BFM-90 and CHOP-like courses in the treatment of anaplastic large cell lymphoma (ALCL). MATERIAL AND METHODS: Twenty-two patients with ALCL participated in the study. The diagnosis was made basing on the findings of clinical, device, morphological, immunohistochemical and molecular-genetic examinations with application of a panel of monoclonal antibodies to CD30, ALK, CD3, CD4, CDS, CD7, CD34, CD15, CD68, CD20, CD45RO, CD45RA, Ki-67. 14 cases of 22 were negative by kinase of anaplastic lymphocytes (ALK-) and 8 were positive (ALK+). Mean age of ALK-ALCL patients was 39.6 +/- 4.1 years, of ALK+ALCL patients - 23.4 +/- 2.6 years. 14 patients were treated by the protocol NHL-BFM-90, 8 were initially treated with other schemes (CHOP, MACOP-B, BEACOPP and others). All 14 patients treated according to NHL-BFM-90 had ALCL stages III-IV with B-symptoms. 12 patients who completed treatment by the above protocol achieved complete remission after the forth course, 2 patients failed the treatment. Of 8 ALCL patients treated initially according to other schemes, a complete remission was achieved in 4 patients (2 had stage II). One of 4 patients with remission had recurrence. Four patients who had failed to achieve complete remission died of the disease progression. CONCLUSION: ALCL occurs more frequently in young and middle-aged patients. The disease has an aggressive course with rapid generalization. For such processes it is more preferable to use a modified protocol NHL-BFM-90.     

NSI+] determinant has a pleiotropic phenotypic manifestation that is modulated by SUP35, SUP45, and VTS1 genes

We recently discovered the novel non-chromosomal determinant in Saccharomyces cerevisiae [NSI ⁺] (nonsense suppression inducer), which causes omnipotent nonsense suppression in strains where the Sup35 N-terminal domain is deleted. [NSI ⁺] possesses yeast prion features and does not correspond to previously identified yeast prion determinants. Here, we show that [NSI ⁺ ] enhances nonsense codon read-through and inhibits vegetative growth in S. cerevisiae. Using a large-scale overexpression screen to identify genes that impact the phenotypic effects of [NSI ⁺], we found that the SUP35 and SUP45 genes encoding the translation termination factors eRF3 and eRF1, respectively, modulate nonsense suppression in [NSI ⁺] strains. The VTS1 gene encodes an NQ-enriched RNA-binding protein that enhances nonsense suppression in [NSI ⁺] and [nsi ⁻] strains. We demonstrate that VTS1 overexpression, like [NSI ⁺] induction, causes translational read-through and growth defects in S. cerevisiae.     

[NSI +]: a novel non-Mendelian nonsense suppressor determinant in Saccharomyces cerevisiae

Non-Mendelian determinants that control heritable traits in yeast are subdivided into two major groups—one that includes DNA- or RNA-based elements and another that comprises protein-based factors that are analogous to mammalian prion. All yeast non-Mendelian determinants show dominant inheritance, and some of them demonstrate cytoplasmic infectivity. Only prions, however, harbor-specific features, such as high frequency of induction following overproduction of prion-encoding protein, loss of the protein’s normal function, and reversible curability. Here, we describe a novel nonchromosomal determinant that, in addition to [PSI ⁺] and [ISP ⁺], is involved in epigenetic control of nonsense suppression. This determinant, which we have designated [NSI ⁺], causes nonsense suppression in the strains bearing the N-terminal-deleted or -modified SUP35 gene, but has no manifestation in the strains with the intact copy of SUP35. [NSI ⁺] shows dominant non-Mendelian inheritance, reversible curability and may be transmitted by cytoduction, albeit with low frequency. Similar to yeast prions, this determinant can be cured by deletion or mutational inactivation of Hsp104. We have shown that [NSI ⁺] does not correspond to the already identified yeast prions. Based on the data obtained, we hypothesize that [NSI ⁺] is a novel prion factor involved in epigenetic control of nonsense suppression.     

Prognostic value of a focal bone marrow lesion in diffuse large B-cell lymphosarcoma

AIM: To study prognostic implications of a focal mature cell lesion of the bone marrow (BM) in patients with diffuse large B cell lymphosarcoma (DBLCL). MATERIAL AND METHODS: 54 patients with histologically confirmed DBLCL were given first-line CHOP and CHOP-like courses from 1996 to 2003. B-cell nature of the tumor was confirmed immunohistochemically, immunophenotypically and with flow fluorimetry. RESULTS: In debute of the disease 16 patients had local involvement of the lymph organs (stage I-II by Enn-Arbor), 21 patients--generalized disease (stage III-IV) and 17 patients--involvement of non-lymphatic organs. Overall 3-year survival in first-line therapy in mature cell lesion of BM was 23%, without it--0%. One-year event-free survival was 34 and 0%, respectively. CONCLUSION: The presence of a focal mature cell lesion of BM in DBLCL patients influences the prognosis. Regarding high frequency of transformation of mature cell lymphoproliferative diseases in DBLCL, focal lesion of BM is an indirect sign of a secondary nature of the disease.