Key Points A subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.

The T-box transcription factor Tpit was identified as a cell-specific factor for expression of the pituitary proopiomelanocortin (POMC) gene. Expression of this factor is exclusively restricted to the pituitary POMC-expressing lineages, the corticotrophs and melanotrophs. We have now determined the role of this factor in pituitary cell differentiation. Tpit is a positive regulator for late POMC cell differentiation and POMC expression, but it is not essential for lineage commitment. The pituitary intermediate lobe normally contains only Tpit-expressing melanotrophs. Inactivation of the Tpit gene results in almost complete loss of POMC-expressing cells in this tissue, which now has a large number of gonadotrophs and a few clusters of Pit-1-independent thyrotrophs. The role of Tpit as a negative regulator of gonadotroph differentiation was confirmed in transgenic gain-of-function experiments. One mechanism to account for the negative role of Tpit in differentiation may be trans-repression between Tpit and the gonadotroph-restricted factor SF1. These data suggest that antagonism between Tpit and SF1 may play a role in establishment of POMC and gonadotroph lineages and that these lineages may arise from common precursors.

We have previously demonstrated that GATA-2 and GATA-3 are expressed in adipocyte precursors and control the preadipocyte-to-adipocyte transition. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor ␥ (PPAR␥) promoter and suppression of its basal activity. In the present study, we demonstrate that both GATA-2 and GATA-3 form protein complexes with CCAAT/enhancer binding protein ␣ (C/EBP␣) and C/EBP␤, members of a family of transcription factors that are integral to adipogenesis. We mapped this interaction to the basic leucine zipper domain of C/EBP␣ and a region adjacent to the carboxyl zinc finger of GATA-2. The interaction between GATA and C/EBP factors is critical for the ability of GATA to suppress adipocyte differentiation. Thus, these results show that in addition to its previously recognized function in suppressing PPAR␥ transcriptional activity, interaction of GATA factors with C/EBP is necessary for their ability to negatively regulate adipogenesis.Adipocyte differentiation is a process controlled by multiple regulators, principally the CCAAT/enhancer binding protein (C/EBP) family of transcription factors and the peroxisome proliferator-activated receptor ␥ (PPAR␥), a nuclear hormone receptor (12, 15). Upon hormonal stimulation, the expression of C/EBP␤ and C/EBP␦ temporally increases (3), followed by expression of PPAR␥ and C/EBP␣ (3, 16). A cooperative interaction between PPAR␥ and C/EBP␣ drives the expression of genes that are necessary for the generation and maintenance of the adipogenic phenotype, such as genes producing morphological changes, lipid accumulation, and insulin sensitivity (22).The C/EBP family of transcription factors contains a highly conserved basic leucine zipper domain (bZip) that mediates homo-or heterodimerization with other isoforms in this protein family. Gain-or loss-of-function studies of preadipocyte cell lines and loss-of-function experiments in vivo all indicate that C/EBP␣ is a key regulator of adipogenesis (6,20,23,25). Furthermore, two other members of this family, C/EBP␤ and C/EBP␦, are also highly expressed in adipose tissue and have been demonstrated to be vital components of the signaling cascade which initiates adipocyte differentiation (13). Clearly, the coordinated activity of these three members of the C/EBP family makes key contributions to adipogenesis.We have previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed predominantly in white and not brown adipose tissue in vivo and that their expression is restricted to preadipocytes and down-regulated upon adipocyte differentiation. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation and trapped cells at the preadipocyte stage, as found when morphology and gene expression were assessed. This effect was mediated, at least in part, through direct binding of PPAR␥ and inhibition of its basal promoter activity. However, ...

Ideally, thrombophilia testing should be tailored to the type of thrombotic event without the influence of anticoagulation therapy or acute phase effects which can give false positive results that may result in long term anticoagulation. However, thrombophilia testing is often performed routinely in unselected patients. We analyzed all consecutive thrombophilia testing orders during the months of October and November 2009 at an academic teaching institution. Information was extracted from electronic medical records for the following: indication, timing, comprehensiveness of tests, anticoagulation therapy at the time of testing, and confirmatory repeat testing, if any. Based on the findings of this analysis, we established local guidelines in May 2013 for appropriate thrombophilia testing, primarily to prevent testing during the acute thrombotic event or while the patient is on anticoagulation. We then evaluated ordering practices 22 months after guideline implementation. One hundred seventy-three patients were included in the study. Only 34% (58/173) had appropriate indications (unprovoked venous or arterial thrombosis or pregnancy losses). 51% (61/119) with an index clinical event were tested within one week of the event. Although 46% (79/173) were found to have abnormal results, only 46% of these had the abnormal tests repeated for confirmation with 54% potentially carrying a wrong diagnosis with long term anticoagulation. Twenty-two months after guideline implementation, there was an 84% reduction in ordered tests. Thus, this study revealed that a significant proportion of thrombophilia testing was inappropriately performed. We implemented local guidelines for thrombophilia testing for clinicians, resulting in a reduction in healthcare costs and improved patient care.

No abstract

Brown adipose tissue (BAT) is a specialized mammalian tissue and a site of adaptive thermogenesis. Although the metabolic functions of brown and white adipocytes are distinct, terminal differentiation of both adipocyte lineages is regulated by wellcharacterized common transcription factors. However, the early stages of adipocyte differentiation and regulation of precursor cells are not well understood. We report here that GATA2 is expressed in brown adipocyte precursors, and its expression is downregulated in a differentiation-dependent manner. Constitutive expression of GATA2 suppressed expression of BAT-specific genes in brown adipocytes, whereas disruption of a GATA2 allele in brown preadipocytes resulted in significantly elevated differentiation and expression of several markers of brown adipogenesis. Collectively, these results show that GATA2 functions to suppress brown adipocyte differentiation, whereas reduction of GATA2 promotes brown adipogenesis.

As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study we compared rates of therapy-induced hypothyroidism in 329 patients with DLBCL treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-6 (IL-6), interleukin-12 (IL-12), and interleukin-15 (IL-15) before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs 1.3%), and we found a statistically significant increase in serum TNF-α in patients with lenalidomide-induced hypothyroidism.

Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both over-expression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.