Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study.

Introduction: Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population.

Reg3α concentrations at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use.

Intestinal microbiome diversity plays an important role in the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GVHD) and influences the outcome of patients after allogeneic stem cell transplantation (ASCT). We analyzed clinical data and blood samples taken preconditioning and on the day of ASCT from 587 patients from 7 German centers of the Mount Sinai Acute GVHD International Consortium, dividing them into single-center test (n = 371) and multicenter validation (n = 216) cohorts. Regenerating islet-derived 3α (Reg3α) serum concentration of day 0 correlated with clinical data as well as urinary 3-indoxylsulfate (3-IS) and Clostridiales group XIVa, indicators of intestinal microbiome diversity.

A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6/2 Mouse Model of Huntington's Disease: Possible Sex-Dependent Signaling.

The R6/2 transgenic mouse model of Huntington's disease (HD) carries several copies of exon1 of the huntingtin gene that contains a highly pathogenic 120 CAG-repeat expansion. We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6/2 mice at a pre-symptomatic (e.g.

Measuring the cellular memory B cell response after vaccination in patients after allogeneic stem cell transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), patients are repetitively vaccinated to reduce the risk of infection caused by the immune deficiency following allogeneic HSCT. By the vaccination of transplanted patients, the humoral memory function can be restored in the majority of cases. It is unknown, however, to what extent memory B cells derived from the donor contribute to the mobilization of antibody-secreting cells and long-term humoral memory in patients after allogeneic HSCT.

Responsive eLearning exercises to enhance student interaction with metabolic pathways.

Successful learning of biochemistry requires students to engage with the material. In the past this often involved students writing out pathways by hand, and more recently directing students to online resources such as videos, songs, and animated slide presentations. However, even these latter resources do not really provide students an opportunity to engage with the material in an active fashion.

The Glutamine-Alanine Repeat Domain of TCERG1 is Required for the Inhibition of the Growth Arrest Activity of C/EBPα.

TCERG1 was characterized previously as a repressor of the transcription factor C/EBPα through a mechanism that involved relocalization of TCERG1 from nuclear speckles to pericentromeric regions. The inhibitory activity as well as the relocalization activity has been demonstrated to lie in the amino terminal half of the protein, which contains several discrete motifs including an imperfect glutamine-alanine (QA) repeat. In the present study, we showed that deletion of this domain completely abrogated the ability of TCERG1 to inhibit the growth arrest activity of C/EBPα.

Monitoring of hematopoietic chimerism by real-time quantitative PCR of micro insertions/deletions in samples with low DNA quantities.

Background: Sensitive and accurate methods to detect hematopoietic chimerism after hematopoietic stem cell transplantation (HSCT) are essential to evaluate engraftment and to monitor response to therapeutic procedures such as donor lymphocyte infusion. Continuous long-term follow up, however, requires large amounts of pre-HSCT samples limiting the application of many widely used techniques for sensitive chimerism monitoring.

Methods: DNAs from 42 normal healthy donors and 16 HSCT donor/recipient pairs were employed to validate the use of allele-specific insertion/deletion (indel) quantitative real-time polymerase chain reaction (qPCR) to quantify chimerism in samples with low amounts of DNA.

TCERG1 inhibits C/EBPα through a mechanism that does not involve sequestration of C/EBPα at pericentromeric heterochromatin.

Transcriptional elongation regulator 1 (TCERG1) is a nuclear protein that participates in multiple events that include regulating the elongation of RNA polymerase II and coordinating transcription and pre-mRNA processing. More recently, we showed that TCERG1 is also a specific inhibitor of the transcription factor CCAAT enhancer binding protein α (C/EBPα). Interestingly, the inhibition of C/EBPα by TCERG1 is associated with the relocalization of TCERG1 from the nuclear speckle compartment to the pericentromeric regions where C/EBPα resides.

The Δ4-desaturation pathway for DHA biosynthesis is operative in the human species: differences between normal controls and children with the Zellweger syndrome.

Background: Docosahexaenoic acid (DHA, 22:6ω3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels.

Nuclear redistribution of TCERG1 is required for its ability to inhibit the transcriptional and anti-proliferative activities of C/EBPalpha.

Transcription elongation regulator 1 (TCERG1) is an inhibitor of transcriptional elongation, and interacts with transcription and splicing factors, suggesting that it assists in coupling and coordinating these two processes. Recently we showed that TCERG1 possesses an additional activity, that being to repress the transactivation and anti-proliferative activities of the transcription factor CCAAT/Enhancer Binding Protein alpha (C/EBPalpha). In the present study, we provide evidence that TCERG1 functions as an inhibitor of C/EBPalpha rather than a transcriptional co-repressor.

Caspase-8 dependent apoptosis induction in malignant myeloid cells by TLR stimulation in the presence of IFN-alpha.

Pro-apoptotic signalling upon toll-like receptor (TLR) stimulation in myeloid cells is normally antagonized by the simultaneous activation of anti-apoptotic pathways. We have previously reported that IFN-alpha can sensitize human monocytes to apoptosis induction by lipopolysaccharide (LPS). Based on these results we investigated whether similarly apoptosis can be cooperatively induced in myeloid tumor cells.

Palifermin as treatment in dose-intense conventional polychemotherapy induced mucositis.

Polychemotherapy or radiation frequently causes oral mucositis. Until now, only supportive options are available. Palifermin, a recombinant form of the human keratinocyte growth factor can avoid mucositis in patients treated with myeloablative polychemotherapy for allogeneic stem cell transplantation.

Identification of a co-repressor that inhibits the transcriptional and growth-arrest activities of CCAAT/enhancer-binding protein alpha.

We used a yeast two-hybrid screening approach to identify novel interactors of CCAAT/enhancer-binding protein alpha (C/EBPalpha) that may offer insight into its mechanism of action and regulation. One clone obtained was that for CA150, a nuclear protein previously characterized as a transcriptional elongation factor. In this report, we show that CA150 is a widely expressed co-repressor of C/EBP proteins.

Troglitazone overcomes doxorubicin-resistance in resistant K562 leukemia cells.

Human myeloid leukemia cells become resistant to doxorubicin (DOX) treatment and this resistance is correlated with an increased glyoxalase 1 (GLO1) expression. Troglitazone (TRG) is an anti-diabetic thiazolidinedione drug previously used to treat insulin-resistance in Type 2 diabetes. We previously showed that TRG down regulates GLO1 gene expression in a number of cell types and reasoned that TRG might be a useful adjunct therapy to overcome DOX resistance.

Effect of overexpression and nuclear translocation of constitutively active PKB-alpha on cellular survival and proliferation in HepG2 cells.

Protein kinase B (Akt/PKB) is a key component in the PI 3-kinase mediated cell survival pathway and has oncogenic transformation potential. Although the over-expression of PKB-alpha can prevent cell death following growth factor withdrawal, the long-term effects of stable over-expression of PKB-alpha on cell survival in the absence of growth factors remain to be resolved. In the present study, we generated HepG2 cells with stable expression of active PKB-alpha and compared its characteristics with HepG2 cells.

Troglitazone reduces heat shock protein 70 content in primary rat hepatocytes by a ubiquitin proteasome independent mechanism.

Troglitazone (TRG) is an antidiabetic agent that increases the insulin sensitivity of target tissues in non-insulin-dependent diabetes mellitus. Therapy with troglitazone has been associated with severe hepatic injury in a small percentage of patients and the mechanism of TRG-induced hepatotoxicity remains unclear. A family of highly conserved stress proteins identified as heat shock proteins (Hsps), are well-known to protect cells against a wide variety of toxic conditions such as extreme temperature changes, oxidative stress and toxic drugs.

Regulation of the glyoxalase pathway in human brain microvascular endothelium: effects of troglitazone and tertiary butylhydroperoxide.

The glyoxalase system, comprised of glyoxalase-I and glyoxalase-II with glutathione as the cofactor, plays an important role in the detoxification of methylglyoxal and other alpha-oxo-aldehydes. Such aldehydes, which increase with hyperglycemia, give rise to advanced glycation end products. The objective of this research was to examine the glyoxalase system in human cerebromicrovascular cells.

Different transcription factor binding arrays modulate the cAMP responsivity of the phosphoenolpyruvate carboxykinase gene promoter.

The cAMP responsiveness of the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter is mediated by a cAMP response unit, which includes three CCAAT/enhancer-binding protein (C/EBPs) sites, and a cAMP response element (CRE). Because both the CRE-binding protein and several C/EBP isoforms can to bind to the CRE with similar affinity, a variety of transcription factor bindings arrays in the cAMP response unit are possible that may affect the protein kinase A (PKA) responsivity of the promoter. To explore this issue, we have designed PEPCK promoter variants that have the native cis-elements within the cAMP response unit replaced with one or more LexA- and/or GAL4-binding sites.

Conserved amino acids within CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) regulate phosphoenolpyruvate carboxykinase (PEPCK) gene expression.

Thyroid hormone and cAMP stimulate transcription of the gene for phosphoenolpyruvate carboxykinase (PEPCK). CCAAT enhancer-binding proteins (C/EBP(alpha) and beta) are involved in multiple aspects of the nutritional, developmental and hormonal regulation of PEPCK gene expression. Previously, we have identified a thyroid hormone response element in the PEPCK promoter and demonstrated that C/EBP proteins bound to the P3(I) site are participants in the induction of PEPCK gene expression by thyroid hormone and cAMP.

CCAAT/enhancer binding proteins: do they possess intrinsic cAMP-inducible activity?

CCAAT/enhancer binding proteins (C/EBPs) are transcription factors that are enriched in tissues which play a central role in energy metabolism, such as adipose and liver. Structure/function analyses of these proteins have identified several transactivation domains, some of which can physically interact with general transcription factors present in the preinitiation complex. C/EBPs are generally considered to be constitutively-acting factors, unlike other transcription factors whose activities can be regulated by covalent modification, binding of a specific ligand, etc.